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Cited by 1,048HER2/EGFR in Cancer ResearchLung Cancer Treatments and MutationsCancer Mechanisms and Therapy

ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics

Open access
Arteaga, Carlos L., Engelman, Jeffrey A.·2014·Cancer Cell
DOI 10.1016/j.ccr.2014.02.025PMC PMC4018830
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Abstract

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.

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

Registry

Crossref · 10.1016/j.ccr.2014.02.025

Cites

223 of 223 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 199 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    Clinical evidence of an association between HER2-Δ16 and resistance to trastuzumab has not been shown.

    “However, clinical evidence of an association between HER2-Δ16 and resistance to trastuzumab has not been shown.”
    Quote in the paperNot a substantial claim
  • Findingreasoning

    The association of PTEN loss with drug resistance in the clinic is less clear.

    “However, the association of PTEN loss with drug resistance in the clinic is less clear.”
    Quote in the paperNot a substantial claim
  • Findingreasoning

    Several of the other combinations do not have straightforward biomarkers for patient selection.

    “However, several of the other combinations do not have straightforward biomarkers for patient selection.”
    Quote in the paperSubstantial claim
  • Premisecitation

    EGFR mutations are primarily localized within two hot spots: overlapping deletions in exon 19 and L858R.

    “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)].”
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  • Interpretationreasoning

    Improvement in survival of patients with HER2 amplified early-stage breast cancer treated with trastuzumab is further evidence linking HER2 with cancer progression.

    “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.”
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    Findingnone given

    Comprehensive studies profiling HER2+ tumors that have progressed on primary anti-HER2 therapies have not been reported.

    “However, comprehensive studies profiling HER2+ tumors that have progressed on primary anti-HER2 therapies have not been reported.”
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    Findingnone given

    In the metastatic setting, EGFR and HER2 inhibitors do not lead to cures, and cancers ultimately develop resistance.

    “However, in the metastatic setting, these inhibitors do not lead to cures, and cancers ultimately develop resistance.”
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    Premisenone given

    Lung cancers with EGFR mutations are most highly associated with adenocarcinoma histology and in patients with a minimal smoking history.

    “Lung cancers with EGFR mutations are most highly associated with adenocarcinoma histology and in patients with a minimal smoking history.”
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    Premisecitation

    Several HER2 mutants have increased signaling activity and are most commonly associated with lung adenocarcinoma, lobular breast, bladder, gastric, and endometrial cancers.

    “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).”
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    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Many ERBB3 mutations are located in the extracellular domain, appear to have oncogenic potential, function in a ligand-independent manner, and require heterodimerization with HER2 for transforming activity.

    “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).”
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    Premisenone given

    EGFR mutations are found in ~8%-10% of Caucasians, but in a higher proportion of East Asians.

    “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.”
    Quote in the paperNot a substantial claim

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    Interpretationcitation

    HER2 amplification was the first reported oncogenic alteration associated with poor outcome in cancer patients, suggesting a causal relationship to cancer virulence.

    “This was the first report of an oncogenic alteration associated with poor outcome in cancer patients, suggesting a causal relationship to cancer virulence.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Antibodies directed against EGFR block growth of A431 cells, demonstrating that EGFR signaling could drive cancer cell growth.

    “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).”
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    Premisecitation

    EGFRvIII exhibits constitutive dimerization, impaired downregulation, and aberrant tyrosine kinase activity, all resulting in enhanced tumorigenicity.

    “EGFRvIII exhibits constitutive dimerization, impaired downregulation, and aberrant tyrosine kinase activity, all resulting in enhanced tumorigenicity (Nishikawa et al., 1994).”
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    ERBB family members have a prominent role in the initiation and maintenance of several solid tumors.

    “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.”
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    Premisecitation

    HER2E-HER2+ tumors had higher frequencies of aneuploidy, somatic mutation, TP53 mutation, and amplification of FGFRs, EGFR, CDK4, and cyclin D1.

    “HER2E-HER2+ tumors had higher frequencies of aneuploidy, somatic mutation, and TP53 mutation, as well as amplification of FGFRs, EGFR, CDK4, and cyclin D1.”
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    Premisecitation

    Cetuximab provides clinical benefit primarily in colorectal cancers that do not harbor KRAS mutations and in those with high expression of EGFR ligands amphiregulin and epiregulin.

    “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).”
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    Premisecitation

    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.

    “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.”
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    Premisecitation

    HER3 but not EGFR is always phosphorylated in human HER2-amplified breast cancers, suggesting it is an obligatory co-biomarker of aberrant HER2 activity and dependence.

    “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.”
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    Interpretationreasoning

    T790M pre-exists in a small fraction of cells, and those cells are selected for during the course of treatment.

    “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).”
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    Premisenone given

    HER2 potently activates ERK signaling but does not bind p85 nor directly activate PI3K/AKT.

    “Although HER2 potently activates ERK signaling, it does not bind p85 nor directly activate PI3K/AKT.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    HER2 mutations may comprise only a portion of the amplified HER2 alleles and therefore exist below the limits of sensitivity of traditional DNA sequencing methods.

    “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).”
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    Premisecitation

    An autocrine loop in ovarian cancer cells and tumors overexpressing NRG1 and HER3; suppression of HER3 with RNAi or a neutralizing HER3 antibody suppressed ovarian cancer growth in laboratory models.

    “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).”
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    Premisecitation

    In wild-type KRAS CRCs that develop resistance to cetuximab, a S492R mutation in the extracellular domain of EGFR interferes with cetuximab binding, but does not interfere with ligand-dependent activation nor abrogates receptor engagement by panitumumab.

    “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)”
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    Premisecitation

    Altered trafficking of EREG to the apical cell surface leads to prolonged EGFR phosphorylation and more proliferative and invasive tumors.

    “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).”
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    Premisecitation

    The Δ16 isoform interacts directly with Src, and treatment with the Src inhibitor dasatinib overcomes the resistance to the antibody conferred by the alternative splicing variant.

    “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).”
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    Premisecitation

    T790M abrogates the inhibitor effects of gefitinib and erlotinib by increasing the affinity of the receptor for ATP, thereby lessening the potency of first-generation EGFR inhibitors.

    “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”
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    Premisecitation

    The combination of MET and EGFR inhibitors is sufficient to block downstream signaling and induce marked tumor regressions in EGFR-mutant NSCLC with MET amplification.

    “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).”
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    • cites Engelman et al., 2007 source

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    Premisecitation

    HER2 mutants are resistant to lapatinib and trastuzumab but sensitive to the covalent HER2 TKI neratinib.

    “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).”
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    • cites Bose et al., 2013

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    Premisecitation

    p95-HER2 is a truncated form of HER2 lacking the trastuzumab binding region, which may arise from alternate transcription initiation sites in HER2.

    “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)”
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    Premisecitation

    TGFα is co-overexpressed with EGFR in lung, colorectal, ovary and head and neck squamous cancers, where it is associated with poor patient prognosis.

    “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).”
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    Premisecitation

    Inducible HER3 shRNA and a HER3 neutralizing antibody inhibit growth of established HER2-amplified xenografts, suggesting HER3 is essential for survival of HER2-dependent tumors.

    “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.”
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    • cites Garrett et al., 2013b

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    Premisecitation

    A NRG1-mediated autocrine loop inducing HER3 activation was discovered in head and neck cancer cells without HER2 amplification; these cells were particularly sensitive to lapatinib.

    “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.”
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    Premisecitation

    The HER2 exon 16 splice variant does not eliminate the trastuzumab epitope but stabilizes HER2 homodimers and prevents their disruption upon binding by the antibody, resulting in trastuzumab resistance in cell lines.

    “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.”
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    • cites Mitra et al., 2009

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    Premisecitation

    High levels of NRG1 and HER4 were found in NSCLC residual tumor cells after cytotoxic chemotherapy; inhibition of HER3/4 signaling increased the magnitude and duration of response to chemotherapy in in vivo models.

    “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).”
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    Premisecitation

    A gene signature of TGFβ activity correlates with resistance to trastuzumab and poor clinical outcome in patients.

    “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).”
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    Study design and conductreasoning

    Most RTK-mediated resistance mechanisms do not necessarily involve genetic activation of the RTK, as mainly protein assays have been employed to measure their levels in tumor tissues.

    “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.”
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    Premisecitation

    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.

    “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).”
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    Premisecitation

    The EphA2 receptor confers resistance to trastuzumab in cell lines, and EphA2 expression predicts poor outcome in patients with HER2+ breast cancer.

    “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.).”
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    Premisecitation

    In the EMILIA and Neo-ALTTO randomized trials in HER2+ breast cancer, patients with PIK3CA mutant tumors did not benefit from lapatinib and capecitabine and from lapatinib and trastuzumab, respectively.

    “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.”
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    Premisecitation

    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.

    “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).”
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    Premisecitation

    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.

    “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).”
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    Premisecitation

    Introduction of PIK3CA mutations into EGFR mutant lung cancer cell lines is sufficient to maintain PI3K signaling and promote resistance.

    “Introduction of PIK3CA mutations into EGFR mutant lung cancer cell lines is sufficient to maintain PI3K signaling and promote resistance (Engelman et al., 2006).”
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    Premisecitation

    A selective ADAM inhibitor, INCB3619, inhibits HER3 signaling and enhances gefitinib-mediated inhibition of EGFR in NSCLC.

    “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).”
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    Premisecitation

    In erlotinib-resistant EGFR mutant lung cancer cells and lapatinib-resistant HER2-amplified breast cancer cells, levels of the AXL RTK were markedly increased.

    “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).”
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    Premisecitation

    The quantity and lytic efficiency of CD16(+) lymphocytes are the major factors affecting the level of ADCC induced by trastuzumab, which correlates with tumor response.

    “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).”
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    Premisecitation

    PTEN was no longer capable of dephosphorylating and suppressing Src in trastuzumab-resistant HER2+ cells, and addition of a Src kinase inhibitor overcame trastuzumab resistance.

    “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).”
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    Premisecitation

    Trastuzumab and pertuzumab are each weak signaling inhibitors, possibly because they incompletely block HER2-containing dimers.

    “Trastuzumab and pertuzumab, in particular, are each weak signaling inhibitors, possibly because they incompletely block HER2-containing dimers (Junttila et al., 2009).”
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    Premisecitation

    Levels of BIM are predictive of response to targeted therapy in EGFR mutant lung cancers, HER2-amplified breast cancers and PIK3CA mutant cancers.

    “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).”
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    Premisecitation

    Addition of a Src TKI partially blocked PI3K/AKT and restored sensitivity to lapatinib.

    “Addition of a Src TKI partially blocked PI3K/AKT and restored sensitivity to lapatinib (Rexer et al., 2011).”
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    Premisecitation

    Treatment with lapatinib leads to an increase in HER2 and HER2-containing dimers at the plasma membrane, and fails to completely and persistently inhibit the HER2 kinase.

    “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).”
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    Premisecitation

    HER2-amplified breast cancer cells with acquired resistance to lapatinib up-regulate ERα which, in turn, induces FoxO3a-mediated transcription of survivin.

    “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).”
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    Clinical experience has validated EGFR and HER2 as effective drug targets.

    “Clinical experience has validated EGFR and HER2 as effective drug targets.”
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  • May combine two claims.

    Premisecitation

    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 well as survival factors such as BCL2 and ERα, thereby mitigating the efficacy of HER2 inhibitors.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Chakrabarty et al., 2012

      Not checked in the free run.

    • cites Chandarlapaty et al., 2011

      Not checked in the free run.

    • cites Garrett et al., 2011

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    KRAS mutant clones fail to down-regulate the ERK pathway in response to cetuximab, underlying the resistance.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    An EGFR mutant cell line made resistant to third-generation EGFR inhibitors developed amplification of ERK and was re-sensitized upon inhibition of MEK.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ercan et al., 2012

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    For both HER2- and EGFR-driven cancers, new treatment paradigms will be necessary to lead to durable remissions or even cures.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Addition of the pan-PI3K inhibitor BKM120 to each combination resulted in inhibition of tumor growth, but only partially and temporarily.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hanker et al., 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Recent advances in technology may help bring 'live' biopsies directly into the laboratory for interrogation.

    “Recent advances in technology may help bring these ‘live’ biopsies directly into the laboratory for interrogation (Liu et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liu et al., 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites von Minckwitz et al., 2009

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Alberto Bardelli, personal communication

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationreasoning

    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 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.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: There are a large number of potential resistance mechanisms.

  • May combine two claims.

    Premisecitation

    The combination of trastuzumab and pertuzumab was shown to be superior to each antibody alone in both neoadjuvant trials in patients with early disease and in patients with advanced disease, as assessed by progression-free survival.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gianni et al., 2012

      Not checked in the free run.

    • cites Baselga et al., 2012b

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The neoadjuvant approach facilitates interrogation of the drug-resistant cancer and the identification of targetable mechanisms potentially driving subsequent metastatic recurrences.

    “This neoadjuvant approach facilitates interrogation of the drug-resistant cancer and the identification of targetable mechanisms potentiallly driving subsequent metastatic recurrences (discussed below).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Turke et al., 2010

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Development of cell lines and patient-derived xenografts from resistant biopsies may facilitate the identification of new therapeutic strategies.

    “the development of cell lines and patient-derived xenografts from resistant biopsies may facilitate the identification of new therapeutic strategies.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Except for patients who experience a complete response, tumor tissue is always available at the time of surgery in a pre-operative approach.

    “except for patients who experience a complete response, tumor tissue is always available at the time of surgery.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    With heterogeneity in HER2 overexpression in the primary tumor, anti-oncogene therapy eliminates the HER2-dependent compartment and enriches for HER2-negative clones.

    “with heterogeneity in HER2 overexpression in the primary tumor, the anti-oncogene therapy eliminates the HER2-dependent compartment and enriches for HER2-negative clones.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Stagg et al., 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    The early delivery of anti-HER2 combinations to patients with treatment-naive HER2+ tumors should at least partially trump acquired drug resistance.

    “the early delivery of these anti-HER2 combinations to patients with treatment-naive HER2+ tumors should at least partially trump acquired drug resistance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    None of these trials utilized third generation EGFR inhibitors, which are the only drugs that appear capable of overcoming T790M.

    “However, none of these trials utilized third generation EGFR inhibitors, which are the only drugs that appear capable of overcoming T790M.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The combination of trastuzumab and lapatinib is superior to each agent alone in both the metastatic and neoadjuvant settings.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Blackwell et al., 2010

      Not checked in the free run.

    • cites Baselga et al., 2012a

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Patient-derived xenografts generated with residual cancers can be used to test novel combinations with activity against drug-resistant cancer that can later be applied to patients on an individual basis.

    “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.”
    Quote in the paperSubstantial 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.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Drug-resistant residual cancers potentially have a similar molecular profile to that of drug-resistant micro-metastases.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Balko et al., 2012

      Not checked in the free run.

    • cites Balko et al., 2013

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Molecular profiling of residual tumors should identify targetable genomic alterations causally associated with resistance to neoadjuvant anti-HER2 therapy.

    “Molecular profiling of these residual tumors should identify these alterations.”
    Quote in the paperSubstantial 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.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The timing of treatment may make a difference.

    “The timing of treatment may also make a difference.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    To cure ERBB-dependent cancers, it will likely be necessary to incorporate therapeutics that are toxic to cancer cells via mechanisms not solely based on suppressing ERBB signaling, associated bypass tracks, and antibodies targeting ERBB receptors to induce ADCC.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim
77 of 77

  • 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).”
11 of 11

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?

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.

  • Third-generation EGFR inhibitor is named inconsistently

    Minor

    The discussion calls the inhibitor "CLO-1686," while the cited clinical-trial reference names it "CO-1686."

1 of 1

Cites

Flagged first, then by citations

4 of the 227 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Ranson, 2013, AZD9291: an irreversible, potent and selective tyrosine kinase inhibitor (TKI) of activating (EGFRm+) and resistance (T790M) mutations in advanced NSCLC, J. Thorac. Oncol., 8, s389

Cited by

Sorted by citations

Related

Authors
Arteaga, C. L., & Engelman, J. A.
Affiliations
  • Vanderbilt University (US)
  • Harvard University (US)
Corresponding author
  • Arteaga, Carlos L.
  • Engelman, Jeffrey A.
ORCID
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2014-03
Volume
25
Issue
3
Pages
282-303
ISSN
1535-6108 (ISSN-L)
DOI
10.1016/j.ccr.2014.02.025
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
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
  • Health Sciences › Medicine › Pathology and Forensic Medicine › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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