ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics
2014; Cell Press; Volume: 25; Issue: 3 Linguagem: Inglês
10.1016/j.ccr.2014.02.025
ISSN1878-3686
AutoresCarlos L. Arteaga, Jeffrey A. Engelman,
Tópico(s)Monoclonal and Polyclonal Antibodies Research
ResumoERBB 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. 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. The ERBB family of transmembrane receptor tyrosine kinases (RTKs) consists of the epidermal growth factor receptor EGFR (ERBB1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4). Binding of ligands to the extracellular domain of EGFR, HER3, and HER4 induces the formation of kinase active hetero-oligomers (Yarden and Sliwkowski, 2001Yarden Y. Sliwkowski M.X. Untangling the ErbB signalling network.Nat. Rev. Mol. Cell Biol. 2001; 2: 127-137Crossref PubMed Scopus (3526) Google Scholar). HER2 does not bind any of the ERBB ligands directly, but it is in a conformation that resembles a ligand-activated state and favors dimerization (Cho et al., 2003Cho H.S. Mason K. Ramyar K.X. Stanley A.M. Gabelli S.B. Denney Jr., D.W. Leahy D.J. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab.Nature. 2003; 421: 756-760Crossref PubMed Scopus (594) Google Scholar, Garrett et al., 2003Garrett T.P. McKern N.M. Lou M. Elleman T.C. Adams T.E. Lovrecz G.O. Kofler M. Jorissen R.N. Nice E.C. Burgess A.W. Ward C.W. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors.Mol. Cell. 2003; 11: 495-505Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar). Activation of HER2 and EGFR induces transphosphorylation of the ERBB dimer partner and stimulates intracellular pathways such as RAS/RAF/MEK/ERK, PI3K/AKT/TOR, Src kinases, and STAT transcription factors (reviewed in Yarden and Pines, 2012Yarden Y. Pines G. The ERBB network: at last, cancer therapy meets systems biology.Nat. Rev. Cancer. 2012; 12: 553-563Crossref PubMed Scopus (93) Google Scholar). Although HER3 can bind ATP and catalyze autophosphorylation, it has a weak kinase activity compared to that of its ERBB coreceptors (Shi et al., 2010Shi F. Telesco S.E. Liu Y. Radhakrishnan R. Lemmon M.A. ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation.Proc. Natl. Acad. Sci. USA. 2010; 107: 7692-7697Crossref PubMed Scopus (136) Google Scholar). However, upon transphosphorylation by another ERBB family member, HER3 serves as an efficient phosphotyrosine scaffold, leading to potent activation of downstream signaling. The specificity and potency of intracellular signaling cascades are determined by the expression of positive and negative regulators, the specific composition of activating ligand(s), receptor dimer constituents, and the array of proteins that associate with the tyrosine phosphorylated C-terminal domain of the ERBB receptors (Avraham and Yarden, 2011Avraham R. Yarden Y. Feedback regulation of EGFR signalling: decision making by early and delayed loops.Nat. Rev. Mol. Cell Biol. 2011; 12: 104-117Crossref PubMed Scopus (128) Google Scholar). 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. This has led to the development and widespread implementation of specific ERBB inhibitors as cancer therapies. In this Perspective, we will focus on the therapeutic approaches for targeting ERBB family members in cancer, with a particular emphasis on HER2-amplified breast cancer and EGFR mutant lung cancer. The first evidence for a role of ERBB2 or HER2 (for human EGFR2) in cancer was inferred from the connection to its rat ortholog, Neu, a mutant cDNA isolated from carcinogen-induced neuroblastomas (Schechter et al., 1984Schechter A.L. Stern D.F. Vaidyanathan L. Decker S.J. Drebin J.A. Greene M.I. Weinberg R.A. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen.Nature. 1984; 312: 513-516Crossref PubMed Scopus (511) Google Scholar). (Please note that in this Perspective, ERBB2 and HER2 will be used when discussing mouse and human ERBB2, respectively.) Although rodent Neu is mutated, human HER2 is typically amplified in human cancers such as breast, gastric, and esophageal cancer (Table 1) . Overexpression of either rat or human wild-type ERBB2 was shown to transform diploid cells. 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., 2000Andrechek E.R. Hardy W.R. Siegel P.M. Rudnicki M.A. Cardiff R.D. Muller W.J. Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis.Proc. Natl. Acad. Sci. USA. 2000; 97: 3444-3449Crossref PubMed Google Scholar, Finkle et al., 2004Finkle D. Quan Z.R. Asghari V. Kloss J. Ghaboosi N. Mai E. Wong W.L. Hollingshead P. Schwall R. Koeppen H. Erickson S. HER2-targeted therapy reduces incidence and progression of midlife mammary tumors in female murine mammary tumor virus huHER2-transgenic mice.Clin. Cancer Res. 2004; 10: 2499-2511Crossref PubMed Scopus (52) Google Scholar). In a seminal study, Slamon et al. found that HER2 is amplified in about 20% of breast cancers (Slamon et al., 1987Slamon D.J. Clark G.M. Wong S.G. Levin W.J. Ullrich A. McGuire W.L. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.Science. 1987; 235: 177-182Crossref PubMed Scopus (5181) Google Scholar). This was the first report of an oncogenic alteration associated with poor outcome in cancer patients, suggesting a causal relationship to cancer virulence. 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. 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).Table 1Alterations of ERBB Receptors and Ligands in Human CancerMoleculeAlterationCancer TypesNotesReferencesEGFRmutation (L858R, etc.)NSCLC (adenocarcinoma)substitutions, deletions and insertionsLynch et al., 2004Lynch T.J. Bell D.W. Sordella R. Gurubhagavatula S. Okimoto R.A. Brannigan B.W. Harris P.L. Haserlat S.M. Supko J.G. Haluska F.G. et al.Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.N. Engl. J. Med. 2004; 350: 2129-2139Crossref PubMed Scopus (5987) Google Scholar, Paez et al., 2004Paez J.G. Jänne P.A. Lee J.C. Tracy S. Greulich H. Gabriel S. Herman P. Kaye F.J. Lindeman N. Boggon T.J. et al.EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.Science. 2004; 304: 1497-1500Crossref PubMed Scopus (5061) Google Scholar, Pao et al., 2004Pao W. Miller V. Zakowski M. Doherty J. Politi K. Sarkaria I. Singh B. Heelan R. Rusch V. Fulton L. et al.EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib.Proc. Natl. Acad. Sci. USA. 2004; 101: 13306-13311Crossref PubMed Scopus (2454) Google ScholarEGFRvIIIgliomadeletion of exons 2–7 in the ectodomainSugawa et al., 1990Sugawa N. Ekstrand A.J. James C.D. Collins V.P. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas.Proc. Natl. Acad. Sci. USA. 1990; 87: 8602-8606Crossref PubMed Google ScholarEGFRamplificationNSCLC (squamous), head and neck, glioma, esophageal, colorectal, anal (?)Yarden and Pines, 2012Yarden Y. Pines G. The ERBB network: at last, cancer therapy meets systems biology.Nat. Rev. Cancer. 2012; 12: 553-563Crossref PubMed Scopus (93) Google ScholarHER2amplificationbreast, gastric, esophagealCancer Genome Atlas Network, 2012Cancer Genome Atlas NetworkComprehensive molecular portraits of human breast tumours.Nature. 2012; 490: 61-70Crossref PubMed Scopus (955) Google ScholarHER2mutationbreast (lobular), lung, gastric, bladder, endometrialunclear whether all those reported are activating or gain of functionCancer Genome Atlas Network, 2012Cancer Genome Atlas NetworkComprehensive molecular portraits of human breast tumours.Nature. 2012; 490: 61-70Crossref PubMed Scopus (955) Google ScholarHER3mutationbreast, gastricJaiswal et al., 2013Jaiswal B.S. Kljavin N.M. Stawiski E.W. Chan E. Parikh C. Durinck S. Chaudhuri S. Pujara K. Guillory J. Edgar K.A. et al.Oncogenic ERBB3 mutations in human cancers.Cancer Cell. 2013; 23: 603-617Abstract Full Text Full Text PDF PubMed Scopus (37) Google ScholarHER4mutationmelanoma, NSCLC, medulloblastomaGilbertson et al., 2001Gilbertson R. Hernan R. Pietsch T. Pinto L. Scotting P. Allibone R. Ellison D. Perry R. Pearson A. Lunec J. Novel ERBB4 juxtamembrane splice variants are frequently expressed in childhood medulloblastoma.Genes Chromosomes Cancer. 2001; 31: 288-294Crossref PubMed Scopus (32) Google Scholar, Prickett et al., 2009Prickett T.D. Agrawal N.S. Wei X. Yates K.E. Lin J.C. Wunderlich J.R. Cronin J.C. Cruz P. Rosenberg S.A. Samuels Y. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4.Nat. Genet. 2009; 41: 1127-1132Crossref PubMed Scopus (149) Google ScholarTGF-αoverexpressionprostate, lung, pancreas, ovary, colon, head and neckandrogen-independent prostate cancer; poor prognosis when associated with high EGFRRubin Grandis et al., 1998Rubin Grandis J. Melhem M.F. Gooding W.E. Day R. Holst V.A. Wagener M.M. Drenning S.D. Tweardy D.J. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival.J. Natl. Cancer Inst. 1998; 90: 824-832Crossref PubMed Google Scholar, Yarden and Sliwkowski, 2001Yarden Y. Sliwkowski M.X. Untangling the ErbB signalling network.Nat. Rev. Mol. Cell Biol. 2001; 2: 127-137Crossref PubMed Scopus (3526) Google ScholarNeuregulin-1overexpressioncolorectal, head and necklinked to sensitivity to ERBB3 inhibitors and resistance to EGFR inhibitorsWilson et al., 2011Wilson T.R. Lee D.Y. Berry L. Shames D.S. Settleman J. Neuregulin-1-mediated autocrine signaling underlies sensitivity to HER2 kinase inhibitors in a subset of human cancers.Cancer Cell. 2011; 20: 158-172Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, Yonesaka et al., 2011Yonesaka K. Zejnullahu K. Okamoto I. Satoh T. Cappuzzo F. Souglakos J. Ercan D. Rogers A. Roncalli M. Takeda M. et al.Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab.Sci. Transl. Med. 2011; 3: 99ra86Crossref PubMed Scopus (104) Google Scholar Open table in a new tab 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 (Cancer Genome Atlas Network, 2012Cancer Genome Atlas NetworkComprehensive molecular portraits of human breast tumours.Nature. 2012; 490: 61-70Crossref PubMed Scopus (955) Google Scholar). HER2E-HER2+ tumors had higher frequencies of aneuploidy, somatic mutation, and TP53 mutation, as well as amplification of FGFRs, EGFR, CDK4, and cyclin D1. 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. It is anticipated that because of these molecular differences, the clinical management of HER2E and luminal subtypes of HER2+ breast cancers will also be different. Finally, not all tumors of the HER2E gene expression subtype are HER2 amplified. One implication of these data is that some breast cancers with a single copy of HER2 harbor an expression signature of HER2 dependence and, as such, may benefit from anti-HER2 therapy. 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 fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) also benefitted from adjuvant trastuzumab (Paik et al., 2008Paik S. Kim C. Wolmark N. HER2 status and benefit from adjuvant trastuzumab in breast cancer.N. Engl. J. Med. 2008; 358: 1409-1411Crossref PubMed Scopus (182) Google Scholar). Somatic mutations in HER2 have been reported in several human cancers (Table 1). Most are missense mutations in the tyrosine kinase and extracellular domains or duplications/insertions in a small stretch within exon 20. HER2 mutations are almost exclusively observed in cancers without HER2 gene amplification. Several of these mutants have increased signaling activity, and are most commonly associated with lung adenocarcinoma and lobular breast, bladder, gastric, and endometrial cancers (Cancer Genome Atlas Network, 2012Cancer Genome Atlas NetworkComprehensive molecular portraits of human breast tumours.Nature. 2012; 490: 61-70Crossref PubMed Scopus (955) Google Scholar). 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., 1984Downward J. Yarden Y. Mayes E. Scrace G. Totty N. Stockwell P. Ullrich A. Schlessinger J. Waterfield M.D. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences.Nature. 1984; 307: 521-527Crossref PubMed Scopus (642) Google Scholar). Subsequently, EGFR overexpression was shown to be transforming in laboratory models, and EGFR gene amplification was reported in a wide range of carcinomas. 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., 1983Kawamoto T. Sato J.D. Le A. Polikoff J. Sato G.H. Mendelsohn J. Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody.Proc. Natl. Acad. Sci. USA. 1983; 80: 1337-1341Crossref PubMed Google Scholar). 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., 1990Sugawa N. Ekstrand A.J. James C.D. Collins V.P. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas.Proc. Natl. Acad. Sci. USA. 1990; 87: 8602-8606Crossref PubMed Google Scholar). EGFRvIII exhibits constitutive dimerization, impaired downregulation, and aberrant tyrosine kinase activity, all resulting in enhanced tumorigenicity (Nishikawa et al., 1994Nishikawa R. Ji X.D. Harmon R.C. Lazar C.S. Gill G.N. Cavenee W.K. Huang H.J. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity.Proc. Natl. Acad. Sci. USA. 1994; 91: 7727-7731Crossref PubMed Scopus (588) Google Scholar). In addition to glioblastoma multiforme (GBM), EGFRvIII has been found in a fraction of breast, lung, head and neck, ovarian, and prostate cancers (Moscatello et al., 1995Moscatello D.K. Holgado-Madruga M. Godwin A.K. Ramirez G. Gunn G. Zoltick P.W. Biegel J.A. Hayes R.L. Wong A.J. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors.Cancer Res. 1995; 55: 5536-5539PubMed Google Scholar). Because its expression is restricted to tumor tissues, EGFRvIII has been therapeutically targeted with specific antibodies and vaccines. There is clinical evidence suggesting that the presence of EGFRvIII can predict clinical responses of GBMs to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib (Haas-Kogan et al., 2005Haas-Kogan D.A. Prados M.D. Tihan T. Eberhard D.A. Jelluma N. Arvold N.D. Baumber R. Lamborn K.R. Kapadia A. Malec M. et al.Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib.J. Natl. 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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 (NSCLCs) (Lynch et al., 2004Lynch T.J. Bell D.W. Sordella R. Gurubhagavatula S. Okimoto R.A. Brannigan B.W. Harris P.L. Haserlat S.M. Supko J.G. Haluska F.G. et al.Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.N. Engl. J. Med. 2004; 350: 2129-2139Crossref PubMed Scopus (5987) Google Scholar, Paez et al., 2004Paez J.G. Jänne P.A. Lee J.C. Tracy S. Greulich H. Gabriel S. Herman P. Kaye F.J. Lindeman N. Boggon T.J. et al.EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.Science. 2004; 304: 1497-1500Crossref PubMed Scopus (5061) Google Scholar, Pao et al., 2004Pao W. Miller V. Zakowski M. Doherty J. Politi K. Sarkaria I. Singh B. Heelan R. Rusch V. Fulton L. et al.EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib.Proc. Natl. Acad. Sci. USA. 2004; 101: 13306-13311Crossref PubMed Scopus (2454) Google Scholar) (Table 1). The discovery was spurred by efforts to understand why occasional NSCLCs were highly sensitive to small-molecule EGFR TKIs. 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., 2009Mok T.S. Wu Y.L. Thongprasert S. Yang C.H. Chu D.T. Saijo N. Sunpaweravong P. Han B. Margono B. Ichinose Y. et al.Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.N. Engl. J. Med. 2009; 361: 947-957Crossref PubMed Scopus (2630) Google Scholar, Rosell et al., 2012Rosell R. Carcereny E. Gervais R. Vergnenegre A. Massuti B. Felip E. Palmero R. Garcia-Gomez R. Pallares C. 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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, 2010Pao W. Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer.Nat. Rev. Cancer. 2010; 10: 760-774Crossref PubMed Scopus (288) Google Scholar). In addition, mutations are also rarely observed elsewhere in the kinase domain, including insertions in exon 20 (Yasuda et al., 2013Yasuda H. Park E. Yun C.H. Sng N.J. Lucena-Araujo A.R. Yeo W.L. Huberman M.S. Cohen D.W. Nakayama S. Ishioka K. et al.Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer.Sci. Transl. Med. 2013; 5: ra177Crossref Scopus (7) Google Scholar). The prevalence of the mutations differs among distinct human populations. They are found in ∼8%–10% of Caucasians, but in a higher proportion of East Asians. Lung cancers with EGFR mutations are most highly associated with adenocarcinoma histology and in patients with a minimal smoking history. Of note, cancers with EGFR mutations often have amplification of the mutant EGFR allele as well (Cappuzzo et al., 2005Cappuzzo F. Varella-Garcia M. Shigematsu H. Domenichini I. Bartolini S. Ceresoli G.L. Rossi E. Ludovini V. Gregorc V. Toschi L. et al.Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients.J. Clin. Oncol. 2005; 23: 5007-5018Crossref PubMed Scopus (275) Google Scholar). Cell culture and transgenic mouse model studies have shown that mutant EGFR has transforming activity (Greulich et al., 2005Greulich H. Chen T.H. Feng W. Jänne P.A. Alvarez J.V. Zappaterra M. Bulmer S.E. Frank D.A. Hahn W.C. Sellers W.R. Meyerson M. 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However, the efficacy of the EGFR antibody cetuximab demonstrates the importance of EGFR signaling in these tumors. Although some reports suggest that EGFR amplification correlates with response to cetuximab (Moroni et al., 2005Moroni M. Veronese S. Benvenuti S. Marrapese G. Sartore-Bianchi A. Di Nicolantonio F. Gambacorta M. Siena S. Bardelli A. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study.Lancet Oncol. 2005; 6: 279-286Abstract Full Text Full Text PDF PubMed Scopus (692) Google Scholar), this alteration is not currently used as a predictive biomarker. Importantly, cetuximab provides clinical benefit primarily in colorectal cancers that do not harbor KRAS mutations (Cunningham et al., 2004Cunningham D. Humblet Y. Siena S. Khayat D. Bleiberg H. Santoro A. Bets D. Mueser M. Harstrick A. 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Jassem J. et al.Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.N. Engl. J. Med. 2006; 354: 567-578Crossref PubMed Scopus (2298) Google Scholar). Despite conflicting reports on the utility of EGFR expression by IHC for patient selection in head and neck cancers (and CRCs), there currently are no validated predictive biomarkers of response to EGFR inhibitors in head and neck cancers (Burtness et al., 2005Burtness B. Goldwasser M.A. Flood W. Mattar B. Forastiere A.A. Eastern Cooperative Oncology GroupPhase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study.J. Clin. Oncol. 2005; 23: 8646-8654Crossref PubMed Scopus (461) Google Scholar, Cunningham et al., 2004Cunningham D. Humblet Y. Siena S. Khayat D. Bleiberg H. Santoro A. Bets D. Mueser M. Harstrick A. 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Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: analysis of data from the EXTREME and CRYSTAL studies.Eur. J. Cancer. 2013; 49: 1161-1168Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, Vermorken et al., 2008Vermorken J.B. Mesia R. Rivera F. Remenar E. Kawecki A. Rottey S. Erfan J. Zabolotnyy D. Kienzer H.R. Cupissol D. et al.Platinum-based chemotherapy plus cetuximab in head and neck cancer.N. Engl. J. Med. 2008; 359: 1116-1127Crossref PubMed Scopus (743) Google Scholar). 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. We speculate that this is so because mutant EGFR activation is not ligand dependent and because TKIs have higher affinity for mutant EGFR than for wild-type EGFR, thus leading to a significant therapeutic window. In contrast, antibodies such as cetuximab are more effective in EGFR wild-type cancers because they are highly effective at blocking ligand-dependent activation of EGFR and are pharmacologically stable. ERBB3 has been linked to cancer, primarily due to its mechanistic role in promoting signaling from oncogenic
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