The DOI matches its Crossref record; 223 of the 227 references it cites were found in a registry or an index; 1 of the 199 sources its claims cite were checked for support.
ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics
Open accessAbstract
ERBB receptors were linked to human cancer pathogenesis approximately three decades ago. Biomedical investigators have since developed substantial understanding of the biology underlying the dependence of cancers on aberrant ERBB receptor signaling. An array of cancer-associated genetic alterations in ERBB receptors has also been identified. These findings have led to the discovery and development of mechanism-based therapies targeting ERBB receptors that have improved outcome for many cancer patients. In this Perspective, we discuss current paradigms of targeting ERBB receptors with cancer therapeutics and our understanding of mechanisms of action and resistance to these drugs. As current strategies still have limitations, we also discuss challenges and opportunities that lie ahead as basic scientists and clinical investigators work toward more breakthroughs.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This Perspective reviews how ERBB receptor alterations (EGFR, HER2, HER3, HER4) drive cancer, how mechanism-based inhibitors work, and how resistance emerges. It argues that overcoming resistance will require combinations targeting the oncogene plus bypass tracks, with attention to tumor evolution and trial design.
Key findings
- HER2 amplification occurs in about 20% of breast cancers and is linked to poor outcome; HER2 mutations are found in several cancers, mostly without HER2 gene amplification, and are resistant to lapatinib/trastuzumab but sensitive to neratinib.
- Activating EGFR mutations define a subset of NSCLC highly responsive to EGFR TKIs, with RECIST response rates of ~55%–75%; mutations are found in ~8%–10% of Caucasians and at higher proportion in East Asians.
- Acquired EGFR TKI resistance commonly involves EGFR T790M, present in at least 50% of biopsies from patients with acquired resistance and detectable in ~35% of pre-treatment biopsies by highly sensitive methods.
- PI3K/AKT pathway alterations occur in approximately 30% of HER2+ breast cancers and can confer resistance to HER2 inhibitors; bypass RTK activation (e.g., MET, IGF-1R, AXL, HER3) and apoptosis/cell-cycle defects also mediate resistance.
Methods
- Design: narrative Perspective/review, not a primary experimental study; it synthesizes preclinical models, clinical trials, and prior literature on ERBB biology and therapeutics.
- Data/sample: no new patient cohort or dataset; examples include transgenic mouse models, cell lines, xenografts, clinical trials, and biopsy programs cited from the literature.
- Main analysis: conceptual synthesis of ERBB oncogene discovery, downstream signaling, mechanisms of action of EGFR/HER2/HER3 inhibitors, resistance mechanisms, and combination strategies.
Limitations
- The paper states that many laboratory resistance studies model single-agent therapy, whereas HER2-directed therapies and EGFR antibodies are often used with chemotherapy in the clinic, so selective pressures may not be recapitulated.
- It states that correlative clinical trials often include chemotherapy as a variable not always considered, and resistance to HER2 antagonist combinations has not been widely modeled.
- It notes that many RTK-mediated resistance mechanisms are measured mainly by protein assays (e.g., IHC for IGF-1R, AXL, EphA2), which do not prove causality; single biopsies may not capture all resistant clones across metastatic sites.
- Evident from the text: as a Perspective, it lacks systematic search methods, formal risk-of-bias assessment, or meta-analysis, and reports no new primary outcomes.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
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Verification
Claims the paper makes
147 Not checked yet · 31 Own interpretation · 18 No basis given · 2 Own method · 1 Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Consistent with these data, blockade of HER3 with the neutralizing antibody MM-121 increases the efficacy of cetuximab in a mouse model of EGFR mutant lung cancer (Schoeberl et al., 2010).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Ligand- and RTK-mediated resistance
What the sources say
- Supportedcites Schoeberl et al., 2010 source
The Results section reports that, in mice with EGFR T790M-L858R lung tumors, adding MM-121 to cetuximab produced a more dramatic and sustained response than cetuximab alone. The Methods section identifies the EGFR-mutant mouse model and the combination-treatment group. This supports the attributed claim. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, clinical evidence of an association between HER2-Δ16 and resistance to trastuzumab has not been shown.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > MECHANISMS OF RESISTANCE TO ERBB INHIBITORS > Intrinsic HER2 alterations
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, the association of PTEN loss with drug resistance in the clinic is less clear.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Intracellular kinases
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, several of the other combinations do not have straightforward biomarkers for patient selection.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Projections to the future: Novel approaches > Monitoring tumor evolution
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“EGFR mutations are primarily localized within two hot spots of the kinase domains, a series of overlapping deletions in exon 19 and a leucine to arginine substitution at amino acid position 858 (L858R) [reviewed in (Pao and Chmielecki, 2010)].”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > EGFR
What the sources say
- Not checked yetcites Pao and Chmielecki, 2010 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Further evidence linking HER2 with cancer progression is the improvement in survival of patients with HER2 amplified early-stage breast cancer treated with the HER2 antibody trastuzumab.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > HER2
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“More recent studies using next-generation sequencing have identified less frequent activating mutations in HER2 in several cancer types without HER2 gene amplification (discussed below).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > HER2
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“It is now well established that lung cancers harboring these EGFR mutations are highly responsive to single-agent EGFR inhibitors with RECIST response rates of ~55%–75% (Mok et al., 2009; Rosell et al., 2012; Sequist et al., 2013b).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > EGFR
What the sources say
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Consistent with this speculation are the results of the NSABP B-31 adjuvant trastuzumab trial, in which 9.7% of patients that did not meet criteria for HER2 overexpression by FISH or IHC also benefitted from adjuvant trastuzumab (Paik et al., 2008).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > HER2
What the sources say
- Not checked yetcites Paik et al., 2008 source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“HER2 mutations are almost exclusively observed in cancers without HER2 gene amplification.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > HER2
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 23
- It may state two separate claims as one. 58
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, comprehensive studies profiling HER2+ tumors that have progressed on primary anti-HER2 therapies have not been reported.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > MECHANISMS OF RESISTANCE TO ERBB INHIBITORS > Intrinsic HER2 alterations
plain- Asserted: passes — The authors put it forward as true.
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- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, in the metastatic setting, these inhibitors do not lead to cures, and cancers ultimately develop resistance.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > STRATEGIES TO OVERCOME RESISTANCE: COMBINATION THERAPIES
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Lung cancers with EGFR mutations are most highly associated with adenocarcinoma histology and in patients with a minimal smoking history.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > EGFR
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“Several of these mutants have increased signaling activity, and are most commonly associated with lung adenocarcinoma, lobular breast, bladder, gastric, and endometrial cancers (Koboldt et al., 2012).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > HER2
What the sources say
- Not checked yetcites Koboldt et al., 2012
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is notable that cetuximab appears to be more effective than EGFR TKIs in cancers with ligand-dependent activation of EGFR, whereas TKIs are more effective in cancers with EGFR mutations.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > EGFR
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Many of the mutations were located in the extracellular domain, and they appear to have oncogenic potential, function in a ligand-independent manner, and require heterodimerization with HER2 for transforming activity (Jaiswal et al., 2013).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > ERBB3 and ERBB4
What the sources say
- Not checked yetcites Jaiswal et al., 2013 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The prevalence of the mutations differs among distinct human populations. They are found in ~8%–10% of Caucasians, but in a higher proportion East Asians.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > EGFR
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This was the first report of an oncogenic alteration associated with poor outcome in cancer patients, suggesting a causal relationship to cancer virulence.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > HER2
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“Early studies by Mendelsohn and colleagues demonstrated that antibodies directed against EGFR block growth of A431 cells, demonstrating that EGFR signaling could drive cancer cell growth and setting the stage for clinical use of EGFR inhibitors (Kawamoto et al., 1983).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > EGFR
What the sources say
- Not checked yetcites Kawamoto et al., 1983
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“EGFRvIII exhibits constitutive dimerization, impaired downregulation, and aberrant tyrosine kinase activity, all resulting in enhanced tumorigenicity (Nishikawa et al., 1994).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > EGFR
What the sources say
- Not checked yetcites Nishikawa et al., 1994
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Over the past several years, it has become evident the ERBB family members have a prominent role in the initiation and maintenance of several solid tumors.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > ERBB family: EGFR, HER2, HER3, HER4
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“HER2E-HER2+ tumors had higher frequencies of aneuploidy, somatic mutation, and TP53 mutation, as well as amplification of FGFRs, EGFR, CDK4, and cyclin D1.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > HER2
What the sources say
- Not checked yetcites Koboldt et al., 2012
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Importantly, cetuximab provides clinical benefit primarily in colorectal cancers that do not harbor KRAS mutations (Cunningham et al., 2004) and in those with high expression of EGFR ligands amphiregulin and epiregulin (Khambata-Ford et al., 2007).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > EGFR
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Luminal-HER2+ breast cancers showed higher expression of a luminal gene cluster including GATA3, BCL2, and ESR1 and harbored a higher rate of GATA3 mutations.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > HER2
What the sources say
- Not checked yetcites Koboldt et al., 2012
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Further, HER3 but not EGFR is always phosphorylated in human HER2-amplified breast cancers (Lee-Hoeflich et al., 2008), suggesting it is an obligatory co-biomarker of aberrant HER2 activity and dependence.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > DOWNSTREAM SIGNALING
What the sources say
- Not checked yetcites Lee-Hoeflich et al., 2008
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“This suggests, but does not prove, that it pre-exists in a small fraction of cells, and that those cells are selected for during the course of treatment (Maheswaran et al., 2008; Rosell et al., 2011).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > MECHANISMS OF RESISTANCE TO ERBB INHIBITORS > Intrinsic EGFR alterations
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Although HER2 potently activates ERK signaling, it does not bind p85 nor directly activate PI3K/AKT.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > DOWNSTREAM SIGNALING
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
In the paper
“One possible reason is that these mutations may comprise only a portion of the amplified HER2 alleles and, therefore, exist below the limits of sensitivity of traditional DNA sequencing methods (Zito et al., 2008).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > MECHANISMS OF RESISTANCE TO ERBB INHIBITORS > Intrinsic HER2 alterations
What the sources say
- Not checked yetcites Zito et al., 2008
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“An autocrine loop has been described in ovarian cancer cells and tumors that overexpress NRG1 and HER3, where suppression of HER3 with RNAi or with a neutralizing HER3 antibody suppressed ovarian cancer growth in laboratory models (Sheng et al., 2010) (Table 1).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > ERBB Ligands
What the sources say
- Not checked yetcites Sheng et al., 2010
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“A small study reported the development of a S492R mutation in the extracellular domain of EGFR that interferes with cetuximab binding, but does not interfere with ligand-dependent activation nor abrogates receptor engagement by panitumumab (Montagut et al., 2012)”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > MECHANISMS OF RESISTANCE TO ERBB INHIBITORS > Intrinsic EGFR alterations
What the sources say
- Not checked yetcites Montagut et al., 2012 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“For example, altered trafficking of EREG to the apical cell surface leads to prolonged EGFR phosphorylation and more proliferative and invasive tumors (Singh et al., 2013).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > ERBB Ligands
What the sources say
- Not checked yetcites Singh et al., 2013
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“The Δ16 isoform was found to interact directly with Src, and treatment with the Src inhibitor dasatinib overcame the resistance to the antibody conferred by the alternative splicing variant (Mitra et al., 2009).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > MECHANISMS OF RESISTANCE TO ERBB INHIBITORS > Intrinsic HER2 alterations
What the sources say
- Not checked yetcites Mitra et al., 2009
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“T790M abrogates the inhibitor effects of gefitinib and erlotinib by increasing the affinity of the receptor for ATP (Yun et al., 2008), thereby lessening the potency of first-generation EGRF inhibitors”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > MECHANISMS OF RESISTANCE TO ERBB INHIBITORS > Intrinsic EGFR alterations
What the sources say
- Not checked yetcites Yun et al., 2008
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The combination of MET and EGFR inhibitors was sufficient to block downstream signaling and induce marked tumor regressions (Engelman et al., 2007; Turke et al., 2010).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Ligand- and RTK-mediated resistance
What the sources say
- Not checked yetcites Engelman et al., 2007 source
- Not checked yetcites Turke et al., 2010
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“These mutants of HER2 are resistant to lapatinib and trastuzumab (Figure 1B) but sensitive to the covalent HER2 TKI neratinib (Bose et al., 2013; Wang et al., 2006).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > MECHANISMS OF RESISTANCE TO ERBB INHIBITORS > Intrinsic HER2 alterations
What the sources say
- Not checked yetcites Bose et al., 2013
- Not checked yetcites Wang et al., 2006
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Anido et al. described p95-HER2, a truncated form of HER2, lacking the trastuzumab binding region, which may arise from alternate transcription initiation sites in HER2 (Anido et al., 2006)”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > MECHANISMS OF RESISTANCE TO ERBB INHIBITORS > Intrinsic HER2 alterations
What the sources say
- Not checked yetcites Anido et al., 2006
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“TGFα is also co-overexpressed with EGFR in lung, colorectal, ovary and head and neck squamous cancers, where it is associated with poor patient prognosis (Grandis et al., 1998; Yarden and Sliwkowski, 2001) (Table 1).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > ERBB Ligands
What the sources say
- Not checked yetcites Grandis et al., 1998
- Not checked yetcites Yarden and Sliwkowski, 2001 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“More recently, an inducible HER3 shRNA (Lee-Hoeflich et al., 2008) and a HER3 neutralizing antibody (Garrett et al., 2013b) were shown to inhibit growth of established HER2-amplified xenografts, further suggesting HER3 is essential for survival of HER2-dependent tumors.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > DOWNSTREAM SIGNALING
What the sources say
- Not checked yetcites Lee-Hoeflich et al., 2008
- Not checked yetcites Garrett et al., 2013b
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“A NRG1-mediated autocrine loop inducing HER3 activation was also discovered in head and neck cancer cells without HER2 amplification. These cells were particularly sensitive to the EGFR/HER2 TKI lapatinib (Wilson et al., 2011), suggesting NRG1-driven tumors depend on HER3 activated by HER2 and/or EGFR.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > ERBB Ligands
What the sources say
- Not checked yetcites Wilson et al., 2011 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“This variant does not eliminate the trastuzumab epitope on HER2, but stabilizes HER2 homodimers and prevents their disruption upon binding by the antibody, resulting in trastuzumab resistance in cell lines.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > MECHANISMS OF RESISTANCE TO ERBB INHIBITORS > Intrinsic HER2 alterations
What the sources say
- Not checked yetcites Mitra et al., 2009
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Finally, Hegde et al. found high levels of NRG1 and its receptor HER4 in NSCLC residual tumor cells that remained after cytotoxic chemotherapy. Inhibition of HER3/4 signaling with a NRG1-blocking antibody increased the magnitude and duration of response to chemotherapy in these in vivo models (Hegde et al., 2013).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > LINKS TO CANCER > ERBB Ligands
What the sources say
- Not checked yetcites Hegde et al., 2013
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Further, a gene signature of TGFβ activity was developed and shown to correlate with resistance to trastuzumab and poor clinical outcome in patients (Wang et al., 2008).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Ligand- and RTK-mediated resistance
What the sources say
- Not checked yetcites Wang et al., 2008
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We should note that most of these RTK-mediated mechanisms do not necessarily involve genetic activation of the RTK, as mainly protein assays (i.e., IHC for IGF-IR, AXL, EphA2, etc.) have been employed to measure their levels in tumor tissues.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Ligand- and RTK-mediated resistance
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Further supporting a role of amplified HER2-HER3 signaling in resistance to EGFR-targeted therapies, colorectal cancer patients with de novo or acquired resistance to cetuximab-based therapy exhibit HER2 amplification in their tumor or high levels of circulating heregulin (Yonesaka et al., 2011).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Ligand- and RTK-mediated resistance
What the sources say
- Not checked yetcites Yonesaka et al., 2011 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The EphA2 receptor has been shown to confer resistance to trastuzumab in cell lines, and EphA2 expression was shown to predict poor outcome patients with HER2+ breast cancer. (Zhuang et al.).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Ligand- and RTK-mediated resistance
What the sources say
- Not checked yetcites Zhuang et al.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In the EMILIA and Neo-ALTTO randomized trials in HER2+ breast cancer, patients with PIK3CA mutant tumors did not benefit from lapatinib and capecitabine (Baselga, 2013b) and from lapatinib and trastuzumab (Baselga, 2013a), respectively.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Intracellular kinases
What the sources say
- Not checked yetcites Baselga, 2013b
- Not checked yetcites Baselga, 2013a
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Overexpression of IGF-1R or an increase in levels of IGF-1R/HER2 heterodimers can potently activate PI3K/AKT signaling and confer resistance to trastuzumab in laboratory studies (Huang et al., 2010).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Ligand- and RTK-mediated resistance
What the sources say
- Not checked yetcites Huang et al., 2010
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Similarly, activation of TGFβ receptors can increase ERBB ligand production and cleavage, particularly TGFα, amphiregulin and heregulin, via activation of the TACE/ADAM17 sheddase; this results in activation of HER3 and PI3K and promotes drug resistance (Wang et al., 2008).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Ligand- and RTK-mediated resistance
What the sources say
- Not checked yetcites Wang et al., 2008
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Introduction of PIK3CA mutations into EGFR mutant lung cancer cell lines is sufficient to maintain PI3K signaling and promote resistance (Engelman et al., 2006).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Intracellular kinases
What the sources say
- Not checked yetcites Engelman et al., 2006
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Along those lines, a selective ADAM inhibitor, INCB3619, which prevents the processing and activation of multiple ERBB ligands including heregulin, inhibits HER3 signaling and enhances gefitinib-mediated inhibition of EGFR in NSCLC (Zhou et al., 2006).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Ligand- and RTK-mediated resistance
What the sources say
- Not checked yetcites Zhou et al., 2006
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Finally, in erlotinib-resistant EGFR mutant lung cancer cells and lapatinib-resistant HER2-amplified breast cancer cells, levels of the AXL RTK were markedly increased (Liu et al., 2009; Zhang et al., 2012).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Ligand- and RTK-mediated resistance
What the sources say
- Not checked yetcites Liu et al., 2009
- Not checked yetcites Zhang et al., 2012 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“A follow-up study found that the quantity and lytic efficiency of CD16(+) lymphocytes are the major factors affecting the level of ADCC induced by trastuzumab. This, in turn, correlates with tumor response (Gennari et al., 2004).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Tumor host factors
What the sources say
- Not checked yetcites Gennari et al., 2004 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In another study, the authors suggest that PTEN was no longer capable of dephosphorylating and suppressing Src in trastuzumab-resistant HER2+ cells, and the addition of a Src kinase inhibitor overcame trastuzumab resistance (Zhang et al., 2011).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Intracellular kinases
What the sources say
- Not checked yetcites Zhang et al., 2011 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Trastuzumab and pertuzumab, in particular, are each weak signaling inhibitors, possibly because they incompletely block HER2-containing dimers (Junttila et al., 2009).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > STRATEGIES TO OVERCOME RESISTANCE: COMBINATION THERAPIES > HER2
What the sources say
- Not checked yetcites Junttila et al., 2009
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Indeed, we observed that levels of the pro-apoptotic BH3-only Bcl2 family member, BIM, are predictive of response to targeted therapy in EGFR mutant lung cancers, HER2-amplified breast cancers and PIK3CA mutant cancers (Faber et al., 2011).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Defects in apoptosis and cell cycle control
What the sources say
- Not checked yetcites Faber et al., 2011 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Addition of a Src TKI partially blocked PI3K/AKT and restored sensitivity to lapatinib (Rexer et al., 2011).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Intracellular kinases
What the sources say
- Not checked yetcites Rexer et al., 2011
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Treatment with lapatinib (and likely other HER2 TKIs) leads to an increase in HER2 and HER2-containing dimers at the plasma membrane, and fails to completely and persistently inhibit the HER2 kinase (Garrett et al., 2011; Scaltriti et al., 2009).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > STRATEGIES TO OVERCOME RESISTANCE: COMBINATION THERAPIES > HER2
What the sources say
- Not checked yetcites Garrett et al., 2011
- Not checked yetcites Scaltriti et al., 2009
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“HER2-amplified breast cancer cells with acquired resistance to lapatinib up-regulate ERα which, in turn, induces FoxO3a-mediated transcription of survivin (Xia et al., 2006).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Defects in apoptosis and cell cycle control
What the sources say
- Not checked yetcites Xia et al., 2006
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Clinical experience has validated EGFR and HER2 as effective drug targets.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > STRATEGIES TO OVERCOME RESISTANCE: COMBINATION THERAPIES
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Moreover, inhibition of the HER2 kinase leads to an initial reduction of PI3K/AKT signaling, which releases negative feedbacks resulting in up-regulation of HER3 and other RTKs as wells as survival factors such as BCL2 and ERα, thereby mitigating the efficacy of HER2 inhibitors(Chakrabarty et al., 2012; Chandarlapaty et al., 2011; Garrett et al., 2011; Muranen et al., 2012; Xia et al., 2006).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > STRATEGIES TO OVERCOME RESISTANCE: COMBINATION THERAPIES > HER2
What the sources say
- Not checked yetcites Chakrabarty et al., 2012
- Not checked yetcites Chandarlapaty et al., 2011
- Not checked yetcites Garrett et al., 2011
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“From a signaling perspective, one would expect that the KRAS mutant clones fail to down-regulate the ERK pathway in response to cetuximab, underlying the resistance.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Intracellular kinases
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“In a second example, an EGFR mutant cell line made resistant to third-generation EGFR inhibitors developed amplification of ERK and was re-sensitized upon inhibition of MEK (Ercan et al., 2012).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > BYPASS TRACK RESISTANCE > Intracellular kinases
What the sources say
- Not checked yetcites Ercan et al., 2012
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For both HER2- and EGFR-driven cancers, it is becoming apparent that new treatment paradigms will be necessary to lead to durable remissions or even cures.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Projections to the future: Novel approaches > Innovative trial designs
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
In the paper
“Addition of the pan-PI3K inhibitor BKM120 to each combination resulted in inhibition of tumor growth, but only partially and temporarily (Hanker et al., 2013).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > STRATEGIES TO OVERCOME RESISTANCE: COMBINATION THERAPIES > HER2
What the sources say
- Not checked yetcites Hanker et al., 2013
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Recent advances in technology may help bring these ‘live’ biopsies directly into the laboratory for interrogation (Liu et al., 2012).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Projections to the future: Novel approaches > Monitoring tumor evolution
What the sources say
- Not checked yetcites Liu et al., 2012
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Clinical experience had suggested that trastuzumab-refractory tumors remained dependent on HER2 as continuing trastuzumab in new treatment regimens beyond progression to trastuzumab demonstrated clinical benefit (von Minckwitz et al., 2009).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > STRATEGIES TO OVERCOME RESISTANCE: COMBINATION THERAPIES > HER2
What the sources say
- Not checked yetcites von Minckwitz et al., 2009
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In colorectal cancers that develop KRAS mutations upon development of resistance, current trials are examining the efficacy of EGFR inhibitors in combination with inhibitors to overcome resistance (Alberto Bardelli, personal communication).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > STRATEGIES TO OVERCOME RESISTANCE: COMBINATION THERAPIES > EGFR
What the sources say
- Not checked yetcites Alberto Bardelli, personal communication
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the large number of potential resistance mechanisms will likely necessitate the use of more drugs than will be tolerable if they are all delivered simultaneously, and each drug is dosed to achieve continual target suppression.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Projections to the future: Novel approaches > Innovative trial designs
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds. It may state two separate claims as one.
- Rests on an assumption: There are a large number of potential resistance mechanisms.
None of the sources cited for this claim have been checked yet.
In the paper
“Similarly, the combination of trastuzumab and pertuzumab was shown to be superior to each antibody alone in both neoadjuvant trials in patients with early disease (Gianni et al., 2012) and in patients with advanced disease, as assessed by progression-free survival (Baselga et al., 2012b).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > STRATEGIES TO OVERCOME RESISTANCE: COMBINATION THERAPIES > HER2
What the sources say
- Not checked yetcites Gianni et al., 2012
- Not checked yetcites Baselga et al., 2012b
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This neoadjuvant approach facilitates interrogation of the drug-resistant cancer and the identification of targetable mechanisms potentiallly driving subsequent metastatic recurrences (discussed below).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Projections to the future: Novel approaches > Monitoring tumor evolution
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“For example, in EGFR mutant lung cancers that are resistant via MET amplification, combined EGFR and MET inhibition is required to suppress downstream PI3K/AKT and MEK/ERK and induce tumor regressions in vivo (Turke et al., 2010).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > STRATEGIES TO OVERCOME RESISTANCE: COMBINATION THERAPIES > EGFR
What the sources say
- Not checked yetcites Turke et al., 2010
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the development of cell lines and patient-derived xenografts from resistant biopsies may facilitate the identification of new therapeutic strategies.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Projections to the future: Novel approaches > Monitoring tumor evolution
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“except for patients who experience a complete response, tumor tissue is always available at the time of surgery.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Projections to the future: Novel approaches > Innovative trial designs
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“with heterogeneity in HER2 overexpression in the primary tumor, the anti-oncogene therapy eliminates the HER2-dependent compartment and enriches for HER2-negative clones.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Projections to the future: Novel approaches > Monitoring tumor evolution
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, resistance to T-DM1 may be due to several reasons, including the sparing of HER2-negative tumor cells within heterogeneous cancers containing HER2+ and HER-negative tumor cells, a scenario not uncommon in clinical practice.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > STRATEGIES TO OVERCOME RESISTANCE: COMBINATION THERAPIES > HER2
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“In this case, anti-PD1 would inhibit IFNγ-activated T cells and anti-CD37 would block CD8+ T cells; both of these T-cell subtypes are required for the adaptive immune response triggered by trastuzumab (Stagg et al., 2011).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > STRATEGIES TO OVERCOME RESISTANCE: COMBINATION THERAPIES > HER2
What the sources say
- Not checked yetcites Stagg et al., 2011 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Some examples have clear biomarkers pointing to specific combinations, such as the use of combined HER2 and PI3K inhibitors for HER2-amplified breast cancers harboring PIK3CA mutations, as well as EGFR and MET inhibitors for EGFR mutant lung cancers harboring MET amplifications.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Projections to the future: Novel approaches > Monitoring tumor evolution
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the early delivery of these anti-HER2 combinations to patients with treatment-naive HER2+ tumors should at least partially trump acquired drug resistance.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Projections to the future: Novel approaches > Innovative trial designs
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, none of these trials utilized third generation EGFR inhibitors, which are the only drugs that appear capable of overcoming T790M.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > STRATEGIES TO OVERCOME RESISTANCE: COMBINATION THERAPIES > EGFR
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, the combination of trastuzumab and lapatinib is superior to each agent alone in both the metastatic (Blackwell et al., 2010) and neoadjuvant settings (Baselga et al., 2012a).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > STRATEGIES TO OVERCOME RESISTANCE: COMBINATION THERAPIES > HER2
What the sources say
- Not checked yetcites Blackwell et al., 2010
- Not checked yetcites Baselga et al., 2012a
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the cases of IGF-IR and AXL, it is quite unlikely that expression of the RTK alone will accurately identify those cancers in which those proteins are driving resistance.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Projections to the future: Novel approaches > Monitoring tumor evolution
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“patient-derived xenografts (PDXs) generated with these residual cancers can be used to test novel combinations with activity against these drug-resistant cancer that can be later applied to patients on an individual basis.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Projections to the future: Novel approaches > Innovative trial designs
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- The authors state this as an assumption: Drug-resistant HER2+ residual cancers in the breast harbor targetable genomic alterations causally associated with resistance to neoadjuvant anti-HER2 therapy.
None of the sources cited for this claim have been checked yet.
In the paper
“potentially, a similar molecular profile to that of drug-resistant micro-metastases that can be interrogated with massive parallel sequencing of DNA extracted from the mastectomy specimen (Balko et al., 2012; Balko et al., 2013).”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Projections to the future: Novel approaches > Innovative trial designs
What the sources say
- Not checked yetcites Balko et al., 2012
- Not checked yetcites Balko et al., 2013
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Molecular profiling of these residual tumors should identify these alterations.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Projections to the future: Novel approaches > Innovative trial designs
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- The authors state this as an assumption: Drug-resistant HER2+ residual cancers in the breast harbor targetable genomic alterations causally associated with resistance to neoadjuvant anti-HER2 therapy.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The timing of treatment may also make a difference.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“to cure ERBB-dependent cancers, we will likely have to incorporate therapeutics that are toxic to cancer cells via mechanisms that are not solely based on suppressing ERBB signaling, the associated bypass tracks, and antibodies targeting ERBB receptors to induce ADCC.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“deploying ERBB targeted combinations early in the natural history of these cancers, i.e., in the adjuvant setting to treat micro-metastatic subclinical disease, may yield better outcomes than treating patients with metastatic disease, where the effect will not be curative.”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
The paper relies on this without support.
Mutant KRAS directly activates ERK.
“However, since mutant KRAS directly activates ERK, cetuximab fails to suppress ERK in these cancers, likely explaining the lack of clinical activity (Ebi et al., 2011).”
The paper relies on this without support.
Other than the immune effects of ERBB antibodies, most of the activity of these drugs is due to suppression of downstream signaling, particularly PI3K/AKT and MEK/ERK.
“Other than the immune effects of ERBB antibodies, it is believed that most of activity of these drugs is due to suppression of downstream signaling, particularly PI3K/AKT and MEK/ERK.”
The paper relies on this without support.
The antitumor activity of HER2 inhibitors depends on inhibition of PI3K-AKT downstream of HER2.
“It is generally accepted that the antitumor activity of HER2 inhibitors depends on inhibition of PI3K-AKT downstream of HER2.”
The paper relies on this without support.
Inhibition of a driver oncogene such as EGFR and HER2 results in proliferation arrest and apoptosis.
“Inhibition of a driver oncogene such as EGFR and HER2 results in proliferation arrest and apoptosis.”
The paper relies on this without support.
HER2 mutations in HER2 gene-amplified breast tumors are very rare.
“To the best of our knowledge, HER2 mutations in HER2 gene-amplified breast tumors are very rare.”
The paper relies on this without support.
At least 50% of biopsies from patients with acquired resistance harbor the T790M mutation.
“At least 50% of biopsies from patients with acquired resistance harbor the T790M mutation.”
The paper relies on this without support.
All currently available HER2 inhibitors target or exploit mechanisms of HER2 function.
“All currently available HER2 inhibitors target or exploit mechanisms of HER2 function.”
The paper relies on this without support.
HER2-amplified breast cancers vary with respect to their addiction to HER2 signaling, although they are grouped together using clinical criteria (FISH, IHC) for HER2 overexpression.
“We also recognize that HER2-amplified breast cancers vary with respect to their addiction to HER2 signaling, although they are grouped together using clinical criteria (FISH, IHC) for HER2 overexpression.”
The paper relies on this without support.
The presence of KRAS mutations predicts for lack of initial response to cetuximab.
“As the presence of KRAS mutations predicts for lack of initial response to cetuximab, these findings underscore the convergence of intrinsic and acquired resistance mechanisms.”
The paper relies on this without support.
There are a large number of potential resistance mechanisms.
“the large number of potential resistance mechanisms will likely necessitate the use of more drugs than will be tolerable if they are all delivered simultaneously, and each drug is dosed to achieve continual target suppression.”
The authors state this as an assumption.
Drug-resistant HER2+ residual cancers in the breast harbor targetable genomic alterations causally associated with resistance to neoadjuvant anti-HER2 therapy.
“we propose ‘drug-resistant’ HER2+ residual cancers in the breast harbor targetable genomic alterations causally associated with resistance to neoadjuvant anti-HER2 therapy (Figure 4).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“ErbB receptor signaling has been shown to promote resistance to a variety of target agents including pan-Tyrosine Kinases (TK), AKT, RAF, MEK, and ERK inhibitors (60)”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [60]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > MECHANISMS OF ACTION OF EGFR AND HER2 INHIBITORS > EGFR
“whereas two drugs with similar properties, AZD9291 and CLO-1686, have been”
§ ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics > References
“First-in-human evaluation of CO-1686, an irreversible, selective, and potent tyrosine kinase inhibitor of EGFR T790M”
Citations
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Research works printed but not linked: 1
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Metadata
- Authors
- Arteaga, C. L., & Engelman, J. A.
- Affiliations
- Vanderbilt University (US)
- Harvard University (US)
- Corresponding author
- Arteaga, Carlos L.
- Engelman, Jeffrey A.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 25
- Issue
- 3
- Pages
- 282-303
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4018830
- OpenAlex
- W2037690883
- Cited by
- 1,048
- References
- 227
- Citations by year
- 2026: 50 · 2025: 65 · 2024: 83 · 2023: 92 · 2022: 98 · 2021: 122 · 2020: 83 · 2019: 89 · 2018: 90 · 2017: 99 · 2016: 75 · 2015: 80 · 2014: 21
- FWCI
- 10.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50 CA98131, R01 CA80195, P50CA127003, P30 CA 68485, R01CA080195, R01 CA140954, P50CA098131, P30CA068485, R01CA164273, R01CA137008)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
- Keywords
- ErbB receptors, HER family, oncogene discovery, cancer therapeutics, drug resistance, genetic alterations, targeted cancer therapy, mechanism of action
- MeSH terms
- Animals, Humans, Neoplasms, Signal Transduction, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Receptor, ErbB-3, Mice, Antibodies, Monoclonal, Humanized, ErbB Receptors, Receptor, ErbB-4
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