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

In the paper

“However, clinical evidence of an association between HER2-Δ16 and resistance to trastuzumab has not been shown.”

In the paper

“However, the association of PTEN loss with drug resistance in the clinic is less clear.”

In the paper

“However, several of the other combinations do not have straightforward biomarkers for patient selection.”

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)].”

What the sources say

• Not checked yetcites Pao and Chmielecki, 2010 source

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.”

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).”

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).”

What the sources say

• Not checked yetcites Mok et al., 2009 source
• Not checked yetcites Rosell et al., 2012 source
• Not checked yetcites Sequist et al., 2013b

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).”

What the sources say

• Not checked yetcites Paik et al., 2008 source

In the paper

“HER2 mutations are almost exclusively observed in cancers without HER2 gene amplification.”

In the paper

“An oncogenic mutation that deletes exons 2–7 in the receptor ectodomain, denoted EGFRvIII, is found in about 40% of high-grade gliomas with wild-type EGFR amplification (Sugawa et al., 1990).”

What the sources say

• Not checked yetcites Sugawa et al., 1990 source

In the paper

“The EGF receptor was originally identified as an oncogene because of its homology to v-ERBB, a retroviral protein that enables the avian erythroblastosis virus to transform chicken cells (Downward et al., 1984).”

What the sources say

• Not checked yetcites Downward et al., 1984 source

In the paper

“Somatic mutations in HER2 have been reported in several human cancers (Table 1).”

What the sources say

• Not checked yetcites Table 1

In the paper

“ERBB3 has been linked to cancer, primarily due to its mechanistic role in promoting signaling from oncogenic HER2 and EGFR (discussed below).”

In the paper

“Cell culture and transgenic mouse model studies have shown that mutant EGFR has transforming activity (Greulich et al., 2005; Ji et al., 2006; Politi et al., 2006).”

What the sources say

• Not checked yetcites Greulich et al., 2005 source
• Not checked yetcites Ji et al., 2006
• Not checked yetcites Politi et al., 2006 source

In the paper

“Of note, cancers with EGFR mutations often have amplification of the mutant EGFR allele as well (Cappuzzo et al., 2005).”

What the sources say

• Not checked yetcites Cappuzzo et al., 2005 source

In the paper

“In a seminal study, Slamon et al. found that HER2 is amplified in about 20% of breast cancers (Slamon et al., 1987).”

What the sources say

• Not checked yetcites Slamon et al., 1987 source

In the paper

“The second most common EGFR variant in GBM is EGFRc958, observed in about 20% of tumors with wild-type EGFR amplification.”

What the sources say

• Not checked yetcites Frederick et al., 2000

In the paper

“A recent study of >500 breast tumors by The Cancer Genome Atlas (TCGA) Network has shed light into the biological heterogeneity of clinical HER2 overexpressing cancers (HER2+ as defined by gene amplification) by further parsing into HER2-enriched (HER2E) and luminal subtypes as defined by gene expression (Koboldt et al., 2012).”

What the sources say

• Not checked yetcites Koboldt et al., 2012

In the paper

“However, somatic mutations scattered throughout the ERBB3 gene were recently identified in subsets of breast and gastric cancers (Table 1).”

What the sources say

• Not checked yetcites Table 1

In the paper

“There is clinical evidence suggesting that the presence of EGFRvIII can predict clinical responses of GBMs to the EGFR TKIs gefitinib and erlotinib (Haas-Kogan et al., 2005; Mellinghoff et al., 2005).”

What the sources say

• Not checked yetcites Haas-Kogan et al., 2005 source
• Not checked yetcites Mellinghoff et al., 2005 source

In the paper

“Similarly, mutations in ERBB4 were identified in cancer, particularly melanoma (Prickett et al., 2009), lung adenocarcinoma (Ding et al., 2008), and medulloblastoma (Gilbertson et al., 2001).”

What the sources say

• Not checked yetcites Prickett et al., 2009 source
• Not checked yetcites Ding et al., 2008 source
• Not checked yetcites Gilbertson et al., 2001 source

In the paper

“The causal role of EGFR in tumorigenesis was further solidified in 2004 when somatic, activating mutations in EGFR were discovered in a subset of non-small cell lung cancers (NSCLC) (Lynch et al., 2004; Paez et al., 2004; Pao et al., 2004) (Table 1).”

What the sources say

• Not checked yetcites Lynch et al., 2004 source
• Not checked yetcites Paez et al., 2004 source
• Not checked yetcites Pao et al., 2004 source

In the paper

“Finally, not all tumors of the HER2E gene expression subtype were HER2 amplified.”

What the sources say

• Not checked yetcites Koboldt et al., 2012

In the paper

“Although rodent Neu is mutated, human HER2 is typically amplified in human cancers such as breast, gastric and esophageal (Table 1).”

What the sources say

• Not checked yetcites Table 1

In the paper

“Consistent with its oncogenic activity, overexpression of wild-type Neu or HER2 under the control of a mammary-specific promoter leads to metastatic mammary tumors in transgenic mice (Andrechek et al., 2000; Finkle et al., 2004).”

What the sources say

• Not checked yetcites Andrechek et al., 2000 source
• Not checked yetcites Finkle et al., 2004 source

In the paper

“Activation of MET by its ligand hepatic growth factor (HGF) was also sufficient to promote resistance through activation of downstream signaling (Yano et al., 2008).”

What the sources say

• Not checked yetcites Yano et al., 2008 source

In the paper

“Patients with metastatic breast cancer harboring cytosolic expression of p95-HER2 exhibit a very low response rate to trastuzumab compared to those patients without p95-HER2 in their tumors (Scaltriti et al., 2007).”

What the sources say

• Not checked yetcites Scaltriti et al., 2007 source

In the paper

“This form of HER2 retains kinase activity”

What the sources say

• Not checked yetcites Anido et al., 2006 source

In the paper

“In transgenic mice, genetic ablation of ERBB3 in the mammary gland via Cre-mediated recombination abrogates ERBB2-driven mammary hyperplasias, DCIS, invasive cancers and metastases (Vaught et al., 2012).”

What the sources say

• Not checked yetcites Vaught et al., 2012 source

In the paper

“HER2 mutations have been found in a small proportion of lung, gastric, colorectal, breast and head and neck cancers (Lee et al., 2006; Ross et al., 2013; Stephens et al., 2004; Willmore-Payne et al., 2006).”

What the sources say

• Not checked yetcites Lee et al., 2006 source
• Not checked yetcites Ross et al., 2013 source
• Not checked yetcites Stephens et al., 2004 source

In the paper

“In EGFR-mutant NSCLC cells with acquired resistance, MET reactivates both PI3K/AKT and MEK/ERK signaling despite the inhibition of EGFR.”

What the sources say

• Not checked yetcites Engelman et al., 2007 source

In the paper

“Thus, many cancers are resistant to single-agent ERBB inhibitors because at least one of these critical downstream pathways is maintained despite inhibition of the targeted receptor.”

In the paper

“Further, significantly enhanced levels of invasiveness are observed when breast cancer cells are incubated with exosomes containing high levels of AREG compared to incubation of cells with exosomes containing low levels of AREG or recombinant EGFR ligands (Higginbotham et al., 2011), suggesting a gain-of-function mode of EGFR signaling that might act in more distant environments.”

What the sources say

• Not checked yetcites Higginbotham et al., 2011 source

In the paper

“In EGFR and HER2 driven cancers, HER3 is an important heterodimer partner because it potently activates the phosphatidylinositide-3 kinase (PI3K)/AKT survival pathway via its six docking sites for the p85 regulatory subunit of PI3K.”

In the paper

“Overproduction of ligands is one mechanism by which cancers aberrantly activate ERBB receptors.”

In the paper

“For example HGF has been found to confer resistance to the BRAF inhibitor vemurafenib in BRAF-mutant melanoma cells (Wilson et al., 2012).”

What the sources say

• Not checked yetcites Wilson et al., 2012 source

In the paper

“A splice variant that eliminates exon 16 in the extracellular domain of the HER2 receptor has also been identified in HER2+ primary breast cancers and cell lines (Kwong and Hung, 1998)”

What the sources say

• Not checked yetcites Kwong and Hung, 1998

In the paper

“In transgenic mouse studies, mice that co-express TGFα and Neu in mammary epithelium developed multifocal mammary cancers that arose after a significantly shorter latency than those expressing either gene alone (Muller et al., 1996).”

What the sources say

• Not checked yetcites Muller et al., 1996 source

In the paper

“HGF-induced signaling through MET was shown to abrogate the action of trastuzumab (Shattuck et al., 2008; Turke et al., 2010).”

What the sources say

• Not checked yetcites Shattuck et al., 2008 source
• Not checked yetcites Turke et al., 2010 source

In the paper

“In EGFR mutant lung cancer, the most common mechanism of acquired resistance to EGFR inhibitors is the development of a mutation in the gatekeeper residue of EGFR, T790M (Kobayashi et al., 2005; Pao et al., 2005).”

What the sources say

• Not checked yetcites Kobayashi et al., 2005 source
• Not checked yetcites Pao et al., 2005 source

In the paper

“Amplification of the MET gene was found in EGFR mutant cancers with acquired resistance to EGFR TKIs but not in pre-treatment biopsies (Bean et al., 2007; Engelman et al., 2007).”

What the sources say

• Not checked yetcites Bean et al., 2007 source
• Not checked yetcites Engelman et al., 2007 source

In the paper

“Thus, HER2-mediated activation of HER3 is essential for stimulation of the PI3K/AKT pathway.”

In the paper

“tumors with p95-HER2 may still be susceptible to kinase inhibition with a TKI, as suggested by the observation that p95-HER2 tumors exhibit a similar response rate to the combination of capecitabine and lapatinib compared to breast cancers expressing full-length HER2 (Scaltriti et al., 2010).”

What the sources say

• Not checked yetcites Scaltriti et al., 2010 source

In the paper

“It is important to appreciate that the same molecular mechanism may cause both types of resistance, underscoring the robustness of the biological principles underlying how cancers evade these therapies.”

In the paper

“Recent studies suggest that highly sensitive methods can detect the T790M mutation in ~35% of pre-treatment biopsies.”

What the sources say

• Not checked yetcites Maheswaran et al., 2008 source
• Not checked yetcites Rosell et al., 2011 source

In the paper

“However, most laboratory studies have modeled resistance to these agents as single therapies, thus not recapitulating the selective pressure of combination therapies applied in the clinic.”

In the paper

“In these cases, inhibition of IGF1R re-sensitized to EGFR inhibition.”

What the sources say

• Not checked yetcites Guix et al., 2008

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).”

What the sources say

• Not checked yetcites Schoeberl et al., 2010 source

In the paper

“Constitutive activation of PI3K, via overexpression of PIK3CA mutants, conferred resistance to the antibody in laboratory studies (Chakrabarty et al., 2010; Eichhorn et al., 2008; Serra et al., 2008).”

What the sources say

• Not checked yetcites Chakrabarty et al., 2010 source
• Not checked yetcites Eichhorn et al., 2008 source
• Not checked yetcites Serra et al., 2008 source

In the paper

“In a subset of EGFR mutant lung cancers, amplification of HER2, presumably involving HER3 reactivation, was also identified as a resistance mechanism to EGFR TKIs (Takezawa et al., 2012).”

What the sources say

• Not checked yetcites Takezawa et al., 2012 source

In the paper

“In laboratory models of HER2-amplified breast cancer treated with trastuzumab, increased levels of EGFR and ERBB ligands led to an increase in active EGFR/HER3 and EGFR/HER2 dimers to promote resistance (Ritter et al., 2007).”

What the sources say

• Not checked yetcites Ritter et al., 2007 source

In the paper

“Further, gene amplification of MET and HGF was reported in a cohort of HER2+ patients who did not respond to trastuzumab and chemotherapy (Minuti et al., 2012).”

What the sources say

• Not checked yetcites Minuti et al., 2012 source

In the paper

“This correlation was not found in patients with early breast cancer treated with adjuvant trastuzumab (Perez et al., 2013).”

What the sources say

• Not checked yetcites Perez et al., 2013 source

In the paper

“Such correlations do not prove that the putative bypass RTK is causal to drug resistance in the clinic or in a particular patient.”

In the paper

“In these cell lines, concurrent treatment with recombinant erythropoietin conferred trastuzumab resistance.”

What the sources say

• Not checked yetcites Liang et al., 2010 source

In the paper

“Similarly, in EGFR mutant cancers, MET amplification leads to resistance to EGFR TKIs through re-activation of HER3 (Engelman et al., 2007).”

What the sources say

• Not checked yetcites Engelman et al., 2007 source

In the paper

“Inhibition of IGF-1R with a neutralizing antibody or a small molecule TKI, or targeting the HER2 kinase with lapatinib was found to overcome IGF-1R-mediated resistance to trastuzumab (Nahta et al., 2007).”

What the sources say

• Not checked yetcites Nahta et al., 2007 source

In the paper

“In patients with HER2+ breast cancer, the concurrent administration of erythropoietin and trastuzumab correlated with a shorter progression-free and overall survival compared to patients not receiving erythropoietin (Liang et al., 2010).”

What the sources say

• Not checked yetcites Liang et al., 2010 source

In the paper

“Similarly, activation of IGFIR, via loss of expression of IGFBP3 and IGFBP4, which encode insulin-like growth factor binding proteins 3 and 4, respectively, maintains PI3K/AKT signaling despite blockade of EGFR and promotes resistance to EGFR inhibitors in multiple cell lines (Guix et al., 2008).”

What the sources say

• Not checked yetcites Guix et al., 2008

In the paper

“Most recently, the erythropoietin (Epo) receptor was found to be co-expressed in cell lines and primary tumors that overexpress HER2.”

What the sources say

• Not checked yetcites Liang et al., 2010 source

In the paper

“Targeting AXL was able to re-sensitize some of these resistant cancers to the original TKI.”

What the sources say

• Not checked yetcites Liu et al., 2009 source
• Not checked yetcites Zhang et al., 2012 source

In the paper

“These include mutation and/or amplification of the genes encoding the PI3K catalytic subunits p110α (PIK3CA) and p110β (PIK3CB), the PI3K regulatory subunit p85α (PIK3R1), the PI3K effectors AKT1, AKT2, and PDK1, and loss of the lipid phosphatases PTEN and INPP4B [reviewed in (Engelman, 2009)].”

What the sources say

• Not checked yetcites Engelman, 2009 source

In the paper

“In addition, inhibition of IGF-IR also suppressed the development of “persistor cells,” the small population of PC9 EGFR mutant cells that survives the initial inhibition of EGFR, described by Settleman and colleagues (Sharma et al., 2010).”

What the sources say

• Not checked yetcites Sharma et al., 2010 source

In the paper

“Somatic alterations in the PI3K/AKT pathway are the most frequent in breast cancer, occurring in approximately 30% of HER2+ tumors.”

What the sources say

• Not checked yetcites Engelman, 2009 source

In the paper

“Using a large-scale siRNA genetic screen, they identified PTEN as the only gene whose knockdown conferred trastuzumab resistance (Berns et al., 2007).”

What the sources say

• Not checked yetcites Berns et al., 2007 source

In the paper

“This is consistent with data showing that trastuzumab is unable to block ligand-induced HER2-containing heterodimers (Agus et al., 2002).”

What the sources say

• Not checked yetcites Agus et al., 2002 source

In the paper

“Thus, MET activation by either gene amplification or ligand stimulation can cause bypass resistance to EGFR and HER2 inhibitors.”

In the paper

“In one early study in patients with metastatic breast cancer, loss or low levels of PTEN correlated with a lower response to trastuzumab (Nagata et al., 2004).”

What the sources say

• Not checked yetcites Nagata et al., 2004 source

In the paper

“Finally, using patient-derived colon cancer xenografts, Bertotti et al. identified HER2 gene amplification as a predictor of resistance to cetuximab among KRAS wild-type tumors (Bertotti et al., 2011).”

What the sources say

• Not checked yetcites Bertotti et al., 2011 source

In the paper

“In a neoadjuvant trial of chemotherapy plus trastuzumab, a high level of IGF-1R expression measured by IHC correlated with a poor clinical response (Harris et al., 2007).”

What the sources say

• Not checked yetcites Harris et al., 2007 source

In the paper

“Patients with ‘hot spot’ PIK3CA mutations and undetectable or low PTEN measured by IHC, exhibited a poorer outcome after treatment with chemotherapy and trastuzumab compared to patients without those alterations (Berns et al., 2007; Dave et al., 2011; Esteva et al., 2010).”

What the sources say

• Not checked yetcites Berns et al., 2007 source
• Not checked yetcites Dave et al., 2011 source
• Not checked yetcites Esteva et al., 2010 source

In the paper

“Thus, one would expect that activating mutations in the PI3K pathway would confer resistance to HER2 inhibitors.”

In the paper

“This may explain the generally short-lived responses of metastatic HER2+ breast cancers to single-agent HER2 inhibitors.”

In the paper

“By performing repeat biopsies and evaluating circulating tumor DNA, investigators observed the emergence of KRAS mutations as a resistance mechanism (Diaz et al., 2012; Misale et al., 2012).”

What the sources say

• Not checked yetcites Diaz et al., 2012 source
• Not checked yetcites Misale et al., 2012 source

In the paper

“Accordingly, elevated levels of survivin and MCL-1 have been found in trastuzumab-resistant cells (Chakrabarty et al., 2013).”

What the sources say

• Not checked yetcites Chakrabarty et al., 2013 source

In the paper

“In this study, although erlotinib or lapatinib inhibited EGFR and HER2 and downstream signaling in EGFR mutant and HER2-amplified cancers, respectively, only those cell lines with high levels of BIM underwent marked apoptosis.”

What the sources say

• Not checked yetcites Faber et al., 2011 source

In the paper

“In addition to reactivation of PI3K, re-activation of ERK signaling can promote resistance to EGFR inhibitors as evidenced by the finding of a BRAF mutation in an EGFR mutant lung cancer with acquired resistance (Ohashi et al., 2012).”

What the sources say

• Not checked yetcites Ohashi et al., 2012 source

In the paper

“Indeed, modulation of levels of p27KIP1 appears to be a common endpoint for several of the resistance pathways noted above, including signaling from IGF-1R and MET (Nahta et al., 2005; Shattuck et al., 2008).”

What the sources say

• Not checked yetcites Nahta et al., 2005 source
• Not checked yetcites Shattuck et al., 2008 source

In the paper

“Polymorphisms in the gene encoding FcγRIII in humans were associated with resistance to trastuzumab in patients with metastatic HER2+ breast cancer (Musolino et al., 2008).”

What the sources say

• Not checked yetcites Musolino et al., 2008 source

In the paper

“Downregulation of the Cdk inhibitor p27KIP1 and a resulting increase in Cdk activity has also been associated with trastuzumab resistance (Nahta et al., 2004; Yakes et al., 2002).”

What the sources say

• Not checked yetcites Nahta et al., 2004 source
• Not checked yetcites Yakes et al., 2002

In the paper

“Accordingly, PIK3CA mutations have been identified in biopsies of EGFR mutant cancers with acquired resistance to EGFR inhibitors (Sequist et al., 2011).”

What the sources say

• Not checked yetcites Sequist et al., 2011 source

In the paper

“As single drugs, however, they do not potently suppress HER2 signaling.”

In the paper

“Cell lines made resistant to trastuzumab by chronic exposure exhibited focal amplification of cyclin E.”

What the sources say

• Not checked yetcites Scaltriti et al., 2011 source

In the paper

“In mice lacking FcγRIII and, thus, deficient in NK cells and macrophages capable of binding the Fc region of trastuzumab, the therapeutic effect of trastuzumab was markedly diminished (Clynes et al., 2000).”

What the sources say

• Not checked yetcites Clynes et al., 2000 source

In the paper

“CDK2 inhibitors reduced growth of these trastuzumab-resistant xenografts (Scaltriti et al., 2011).”

What the sources say

• Not checked yetcites Scaltriti et al., 2011 source

In the paper

“BIM protein normally is induced following inhibition of EGFR and HER2 in these cancers.”

What the sources say

• Not checked yetcites Faber et al., 2011 source

In the paper

“This suggests that BIM levels are a biomarker predictive of response to a TKI in an oncogene-addicted cancer.”

In the paper

“Src is thought to mediate resistance in part via phosphorylation and inhibition of PTEN, leading to constitutive PI3K signaling (Liang et al., 2010).”

What the sources say

• Not checked yetcites Liang et al., 2010 source

In the paper

“In HER2+ breast cancer cells, inhibition of HER2-PI3K reduces survivin expression resulting in apoptosis.”

In the paper

“In turn, high survivin levels allow for escape from lapatinib.”

What the sources say

• Not checked yetcites Xia et al., 2006 source

In the paper

“In the same study, PBMCs from patients with FCGR3 polymorphisms associated with an improved outcome after trastuzumab induce a stronger trastuzumab-mediated ADCC in vitro.”

What the sources say

• Not checked yetcites Musolino et al., 2008 source

In the paper

“Similarly, a report found that PTEN loss may be associated with resistance to EGFR inhibitors (Sos et al., 2009).”

What the sources say

• Not checked yetcites Sos et al., 2009 source

In the paper

“Other groups have reported similar results in EGFR mutant lung cancers (Ng et al., 2012) and HER2 gene-amplified breast cell lines with and without activating mutations (Tanizaki et al., 2011).”

What the sources say

• Not checked yetcites Ng et al., 2012
• Not checked yetcites Tanizaki et al., 2011 source

In the paper

“We should note, however, that a large trial of trastuzumab-based adjuvant chemotherapy in patients with early HER2+ breast cancer did not show an association between FCGR3A and FCGR2A polymorphisms with patient outcome (Hurvitz et al., 2012)”

What the sources say

• Not checked yetcites Hurvitz et al., 2012 source

In the paper

“Src activity is also involved in the resistance conferred by the Δ16 HER2 isoform and the EpoR (Mitra et al., 2009).”

What the sources say

• Not checked yetcites Mitra et al., 2009 source

In the paper

“Resistance was associated with recovery of PI3K/AKT signaling despite inhibition of HER2.”

What the sources say

• Not checked yetcites Rexer et al., 2011 source

In the paper

“In HER2+ breast cancer cells with acquired resistance to lapatinib, up-regulation of SFK activity, particularly Yes, was observed in several resistant cell lines.”

What the sources say

• Not checked yetcites Rexer et al., 2011 source

In the paper

“Host factors that affect the immunomodulatory function of trastuzumab can also contribute to trastuzumab resistance.”

In the paper

“In cancers with concurrent PIK3CA mutant cells, however, both the growth inhibitory effect and induction of BIM following treatment with lapatinib were blunted (Tanizaki et al., 2011).”

What the sources say

• Not checked yetcites Tanizaki et al., 2011 source

In the paper

“Survivin, a member of the inhibitor of apoptosis (IAP) protein family that inhibits the activity of caspases, has been shown to be a point of convergence of several pathways that can lead to resistance to HER2 inhibitors.”

In the paper

“Further, in a cohort of patients with HER2+ breast cancers treated with trastuzumab, amplification of cyclin E was associated with a diminished clinical response.”

What the sources say

• Not checked yetcites Scaltriti et al., 2011 source

In the paper

“Therefore, alterations in the normal apoptotic machinery can also induce resistance to EGFR- and HER2-targeted therapies.”

In the paper

“the increasing use of neoadjuvant anti-HER2 therapy in patients with newly diagnosed HER2+ breast cancers provides a novel platform for discovery of mechanisms of resistance and tumor heterogeneity.”

In the paper

“Supporting this possibility, a recent study showed that transgenic mammary tumors expressing HER2 and PIK3CAH1047R were completely resistant to the combinations of trastuzumab plus pertuzumab and trastuzumab plus lapatinib.”

What the sources say

• Not checked yetcites Hanker et al., 2013 source

In the paper

“these patients exhibit a shorter relapse-free survival compared to those with residual tumors that remain HER2 amplified (Hurley et al., 2006; Mittendorf et al., 2009).”

What the sources say

• Not checked yetcites Hurley et al., 2006 source
• Not checked yetcites Mittendorf et al., 2009 source

In the paper

“These ‘drug resistant’ residual cancers should harbor mechanisms and/or biomarkers of resistance to the primary therapy”

What the sources say

• Not checked yetcites Balko et al., 2012 source
• Not checked yetcites Balko et al., 2013

In the paper

“In similar examples of resistance mediated by IGF-IR and AXL, inhibition of the bypass RTK in combination with the EGFR is needed to overcome resistance (Cortot et al., 2013; Guix et al., 2008; Zhang et al., 2012).”

What the sources say

• Not checked yetcites Cortot et al., 2013 source
• Not checked yetcites Guix et al., 2008
• Not checked yetcites Zhang et al., 2012 source

In the paper

“Achievement of a pathological complete response (path CR) in the breast and axillary lymph nodes after neoadjuvant trastuzumab or chemotherapy has been associated with improved long-term outcome (Gianni et al., 2010; Liedtke et al., 2008).”

What the sources say

• Not checked yetcites Gianni et al., 2010 source
• Not checked yetcites Liedtke et al., 2008 source

In the paper

“This has been employed in early clinical trials that have combined EGFR inhibitors with MET inhibitors, PI3K inhibitors and IGF-IR inhibitors (Table 3).”

What the sources say

• Not checked yetcites Table 3

In the paper

“non-invasive measures such as molecular interrogation of circulating tumor cells or plasma DNA may help capture the heterogeneity of resistance in patients, as was done to identify the development of KRAS mutations in colorectal cancers that acquire resistance to cetuximab (Diaz et al., 2012; Misale et al., 2012).”

What the sources say

• Not checked yetcites Diaz et al., 2012 source
• Not checked yetcites Misale et al., 2012 source

In the paper

“Finally, T-DM1, trastuzumab and pertuzumab cannot bind p95-HER2 and, thus, would be inactive against tumor cells with an abundance of cytosolic fragments of HER2.”

In the paper

“The newer third generation EGFR TKIs that suppress T790M are showing remarkable progress in this subset of cancers (Ranson et al., 2013; Sequist et al., 2013a; Soria et al., 2013).”

What the sources say

• Not checked yetcites Ranson et al., 2013
• Not checked yetcites Sequist et al., 2013a
• Not checked yetcites Soria et al., 2013

In the paper

“Along the same lines, neratinib in combination with the TORC1 inhibitor temsirolimus recently demonstrated clinical activity in HER2 mutant lung cancers (Gandhi et al., 2014).”

What the sources say

• Not checked yetcites Gandhi et al., 2014 source

In the paper

“some patients with HER2+ tumors convert to HER2-negative following neoadjuvant trastuzumab and chemotherapy”

What the sources say

• Not checked yetcites Hurley et al., 2006 source
• Not checked yetcites Mittendorf et al., 2009 source

In the paper

“patients with HER2+ tumors that change to HER2-negative upon primary anti-HER2 therapy are at a high risk of early recurrence.”

In the paper

“Recently, the FDA approved the HER2 antibody pertuzumab as neoadjuvant treatment in patients with HER2+ early breast cancer (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm370393.htm).”

What the sources say

• Not checked yetcites http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm370393.htm

In the paper

“the FDA recently proposed that randomized neoadjuvant trials can be considered for accelerated drug approval using path CR as a surrogate that is ‘reasonably likely to predict longer term benefit,’ at least for some subtypes of breast cancer, particularly the HER2+ subtype (Prowell and Pazdur, 2012).”

What the sources say

• Not checked yetcites Prowell and Pazdur, 2012

In the paper

“More recent data suggest that blockade of mTOR downstream HER2 with the TORC1 inhibitor everolimus, while maintaining trastuzumab therapy, can induce clinical responses in HER2+ cancers that have progressed on trastuzumab (Hurvitz et al., 2013; Morrow et al., 2011; O’Regan, 2013).”

What the sources say

• Not checked yetcites Hurvitz et al., 2013 source
• Not checked yetcites Morrow et al., 2011 source
• Not checked yetcites O’Regan, 2013

In the paper

“Preclinical studies suggest panitumumab may overcome this type of resistance (Montagut et al., 2012).”

What the sources say

• Not checked yetcites Montagut et al., 2012 source

In the paper

“the (acquired) alterations identified in a single biopsy may not reflect all of the resistant clones in multiple metastatic sites in an individual patient (Bean et al., 2007; Engelman et al., 2007; Turke et al., 2010).”

What the sources say

• Not checked yetcites Bean et al., 2007 source
• Not checked yetcites Engelman et al., 2007 source
• Not checked yetcites Turke et al., 2010 source

In the paper

“the combination of pertuzumab and trastuzumab was superior to trastuzumab alone.”

What the sources say

• Not checked yetcites NeoSphere
• Not checked yetcites TRYPHAENA

In the paper

“In general, combinations that overcome resistance to EGFR inhibitors have generally required continued inhibition of EGFR combined with a drug that blocks the bypass track [reviewed in (Niederst and Engelman, 2013)].”

What the sources say

• Not checked yetcites Niederst and Engelman, 2013