Targeting ADAMS and ERBBs in lung cancer
2006; Cell Press; Volume: 10; Issue: 1 Linguagem: Inglês
10.1016/j.ccr.2006.06.012
ISSN1878-3686
AutoresNancy E. Hynes, Thomas Schlange,
Tópico(s)Monoclonal and Polyclonal Antibodies Research
ResumoAberrant ERBB receptor activity contributes to the development of many human cancers. Receptor overexpression, kinase domain (KD) mutations, and autocrine ligand production contribute to ERBB activation in human tumors. ERBB-targeted tyrosine kinase inhibitors (TKIs) and monoclonal antibodies are used in cancer treatment; however, clinical hurdles, including patient selection and TKI resistance, need to be overcome in order to optimize therapy. This minireview will discuss recent findings on possible mechanisms leading to ERBB-targeted therapy resistance and potential means to overcome them. Aberrant ERBB receptor activity contributes to the development of many human cancers. Receptor overexpression, kinase domain (KD) mutations, and autocrine ligand production contribute to ERBB activation in human tumors. ERBB-targeted tyrosine kinase inhibitors (TKIs) and monoclonal antibodies are used in cancer treatment; however, clinical hurdles, including patient selection and TKI resistance, need to be overcome in order to optimize therapy. This minireview will discuss recent findings on possible mechanisms leading to ERBB-targeted therapy resistance and potential means to overcome them. The ERBB receptor-ligand network comprises four receptors, EGFR, ERBB2, ERBB3, and ERBB4; and multiple ligands, the EGF-related peptides (Yarden and Sliwkowski, 2001Yarden Y. Sliwkowski M.X. Nat. Rev. Mol. Cell Biol. 2001; 2: 127-137Crossref PubMed Scopus (5264) Google Scholar). ERBB receptors are activated in response to peptide binding, leading to ERBB receptor homo- and heterodimerization (Holbro and Hynes, 2004Holbro T. Hynes N.E. Annu. Rev. Pharmacol. Toxicol. 2004; 44: 195-217Crossref PubMed Scopus (471) Google Scholar). There are three ligand groups: EGF, TGF-α, amphiregulin, and epigen, which bind EGFR; BTC, HB-EGF, and epiregulin, which bind EGFR or ERBB4; and neuregulins (NRGs, also known as heregulins [HRG]), which bind ERB3 and ERBB4. Despite the fact that none of the EGF-related peptides binds ERBB2, this receptor is the preferred dimerization partner for the other ligand-activated ERBBs (Graus-Porta et al., 1997Graus-Porta D. Beerli R.R. Daly J.M. Hynes N.E. EMBO J. 1997; 16: 1647-1655Crossref PubMed Scopus (1258) Google Scholar). Aberrant EGFR and ERBB2 activity contributes to human cancer. Numerous clinical studies have implicated these receptors in the pathology of specific tumor types (Nicholson et al., 2001Nicholson R.I. Gee J.M. Harper M.E. Eur. J. Cancer. 2001; 37: S9-S15Abstract Full Text Full Text PDF PubMed Google Scholar, Ross et al., 2003Ross J.S. Fletcher J.A. Linette G.P. Stec J. Clark E. Ayers M. Symmans W.F. Pusztai L. Bloom K.J. Oncologist. 2003; 8: 307-325Crossref PubMed Scopus (499) Google Scholar). The three major mechanisms leading to ERBB activation in cancer are gene amplification, altered ligand expression, and mutations in the receptor kinase or extracellular domain (Hynes and Lane, 2005Hynes N.E. Lane H.A. Nat. Rev. Cancer. 2005; 5: 341-354Crossref PubMed Scopus (2528) Google Scholar). Intense efforts have gone into developing ERBB-targeted inhibitors, focusing either on the extracellular domain with antibody-based approaches or on blockade of the intracellular kinase domain (KD) with tyrosine kinase inhibitors (TKIs) (Baselga and Arteaga, 2005Baselga J. Arteaga C.L. J. Clin. Oncol. 2005; 23: 2445-2459Crossref PubMed Scopus (642) Google Scholar, Blackhall et al., 2006Blackhall F. Ranson M. Thatcher N. Lancet Oncol. 2006; 7: 499-507Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, Hynes and Lane, 2005Hynes N.E. Lane H.A. Nat. Rev. Cancer. 2005; 5: 341-354Crossref PubMed Scopus (2528) Google Scholar). A mechanistic understanding of how these inhibitors impact on tumor cells will be essential to further enhance the current clinical successes (see, for example, Piccart-Gebhart et al., 2005Piccart-Gebhart M.J. Procter M. Leyland-Jones B. Goldhirsch A. Untch M. Smith I. Gianni L. Baselga J. Bell R. Jackisch C. et al.N. Engl. J. Med. 2005; 353: 1659-1672Crossref PubMed Scopus (3944) Google Scholar). Furthermore, in order to improve patient selection optimization of factors that predict response or resistance to a specific therapeutic must continue. Two papers in this issue of Cancer Cell shed more light on these problems (Wang et al., 2006Wang S.E. Narasanna A. Perez-Torres M. Xiang B. Wu F.Y. Yang S. Carpenter G. Gazdar A.F. Muthuswamy S.K. Arteaga C.L. Cancer Cell. 2006; (this issue)Google Scholar, Zhou et al., 2006Zhou B.-B.S. Peyton M. He B. Liu C. Girard L. Caudler E. Lo Y. Baribaud F. Mikami I. Reguart N. et al.Cancer Cell. 2006; (this issue)Google Scholar). We will briefly present some background before discussing these papers. The first large-scale clinical trials using EGFR TKIs were carried out in non-small cell lung cancer (NSCLC) patients. The overall response rate to the inhibitors was low (reviewed in Blackhall et al., 2006Blackhall F. Ranson M. Thatcher N. Lancet Oncol. 2006; 7: 499-507Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). However, the first somatic mutations in the KD of EGFR were discovered in tumors from those patients who were sensitive to the EGFR-selective TKIs gefitinib and erlotinib; >80% (n = 31) of the responders had KD mutations (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.N. Engl. J. Med. 2004; 350: 2129-2139Crossref PubMed Scopus (9490) Google Scholar, Paez et al., 2004Paez J.G. Janne P.A. Lee J.C. Tracy S. Greulich H. Gabriel S. Herman P. Kaye F.J. Lindeman N. Boggon T.J. et al.Science. 2004; 304: 1497-1500Crossref PubMed Scopus (8027) 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.Proc. Natl. Acad. Sci. USA. 2004; 101: 13306-13311Crossref PubMed Scopus (3719) Google Scholar). Although to a lower extent, KD mutations in ERBB2 have also been detected in NSCLC (Figure 1 and Table 1) (Stephens et al., 2004Stephens P. Hunter C. Bignell G. Edkins S. Davies H. Teague J. Stevens C. O'Meara S. Smith R. Parker A. et al.Nature. 2004; 431: 525-526Crossref PubMed Scopus (17) Google Scholar, Shigematsu et al., 2005Shigematsu H. Takahashi T. Nomura M. Majmudar K. Suzuki M. Lee H. Wistuba I.I. Fong K.M. Toyooka S. Shimizu N. et al.Cancer Res. 2005; 65: 1642-1646Crossref PubMed Scopus (555) Google Scholar, Takano et al., 2005Takano T. Ohe Y. Sakamoto H. Tsuta K. Matsuno Y. Tateishi U. Yamamoto S. Nokihara H. Yamamoto N. Sekine I. et al.J. Clin. Oncol. 2005; 23: 6829-6837Crossref PubMed Scopus (665) Google Scholar, Lee et al., 2006aLee J.W. Soung Y.H. Kim S.Y. Nam S.W. Park W.S. Wang Y.P. Jo K.H. Moon S.W. Song S.Y. Lee J.Y. et al.Cancer Lett. 2006; 237: 89-94Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, Sasaki et al., 2006Sasaki H. Shimizu S. Endo K. Takada M. Kawahara M. Tanaka H. Matsumura A. Iuchi K. Haneda H. Suzuki E. et al.Int. J. Cancer. 2006; 118: 180-184Crossref PubMed Scopus (147) Google Scholar). Needless to say, the pattern of response to ERBB-targeted TKIs and EGFR mutation status have been closely monitored during the past few years. Newer studies reported response rates for NSCLC patients with EGFR KD mutations ranging from 16% (Tsao et al., 2005Tsao M.S. Sakurada A. Cutz J.C. Zhu C.Q. Kamel-Reid S. Squire J. Lorimer I. Zhang T. Liu N. Daneshmand M. et al.N. Engl. J. Med. 2005; 353: 133-144Crossref PubMed Scopus (1666) Google Scholar) to 65% (Johnson and Janne, 2005Johnson B.E. Janne P.A. J. Clin. Oncol. 2005; 23: 6813-6816Crossref PubMed Scopus (47) Google Scholar). These wide differences might reflect diverse patient populations. The expression level of EGFR has also been associated with gefitinib and erlotinib response (Cappuzzo et al., 2005aCappuzzo F. Hirsch F.R. Rossi E. Bartolini S. Ceresoli G.L. Bemis L. Haney J. Witta S. Danenberg K. Domenichini I. et al.J. Natl. Cancer Inst. 2005; 97: 643-655Crossref PubMed Scopus (1450) Google Scholar, Takano et al., 2005Takano T. Ohe Y. Sakamoto H. Tsuta K. Matsuno Y. Tateishi U. Yamamoto S. Nokihara H. Yamamoto N. Sekine I. et al.J. Clin. Oncol. 2005; 23: 6829-6837Crossref PubMed Scopus (665) Google Scholar, Tsao et al., 2005Tsao M.S. Sakurada A. Cutz J.C. Zhu C.Q. Kamel-Reid S. Squire J. Lorimer I. Zhang T. Liu N. Daneshmand M. et al.N. Engl. J. Med. 2005; 353: 133-144Crossref PubMed Scopus (1666) Google Scholar, Shepherd et al., 2005Shepherd F.A. Rodrigues Pereira J. Ciuleanu T. Tan E.H. Hirsh V. Thongprasert S. Campos D. Maoleekoonpiroj S. Smylie M. Martins R. et al.N. Engl. J. Med. 2005; 353: 123-132Crossref PubMed Scopus (4902) Google Scholar). However, objective responses to TKIs have also been observed in the absence of EGFR KD mutations or overexpression (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.Proc. Natl. Acad. Sci. USA. 2004; 101: 13306-13311Crossref PubMed Scopus (3719) Google Scholar, Tsao et al., 2005Tsao M.S. Sakurada A. Cutz J.C. Zhu C.Q. Kamel-Reid S. Squire J. Lorimer I. Zhang T. Liu N. Daneshmand M. et al.N. Engl. J. Med. 2005; 353: 133-144Crossref PubMed Scopus (1666) Google Scholar, Takano et al., 2005Takano T. Ohe Y. Sakamoto H. Tsuta K. Matsuno Y. Tateishi U. Yamamoto S. Nokihara H. Yamamoto N. Sekine I. et al.J. Clin. Oncol. 2005; 23: 6829-6837Crossref PubMed Scopus (665) Google Scholar), suggesting that other factors also contribute to TKI sensitivity. These clinical studies have led to intense efforts, first to clarify if ERBB KD mutations and/or additional factors predict TKI response, and second, to characterize the role of mutant ERBBs in cancer biology.Table 1Frequency of ERBB2 kinase domain mutations in various cancersCancerFrequencyRemarksReferenceNSCLC5/120 (4.2%), 5/51 (9.8%)adenocarcinoma, insertions in exon 20 (4/5), L755P in exon 19Stephens et al., 2004Stephens P. Hunter C. Bignell G. Edkins S. Davies H. Teague J. Stevens C. O'Meara S. Smith R. Parker A. et al.Nature. 2004; 431: 525-526Crossref PubMed Scopus (17) Google Scholar11/671 (1.6%), 11/394 (2.8%)adenocarcinoma, in-frame duplications/insertions in exon 20Shigematsu et al., 2005Shigematsu H. Takahashi T. Nomura M. Majmudar K. Suzuki M. Lee H. Wistuba I.I. Fong K.M. Toyooka S. Shimizu N. et al.Cancer Res. 2005; 65: 1642-1646Crossref PubMed Scopus (555) Google Scholar1/80 (1.3%)tumor cell lines, (+) from adenocarcinoma, in-frame duplications/insertions in exon 200/66gefitinib-treated patientsTakano et al., 2005Takano T. Ohe Y. Sakamoto H. Tsuta K. Matsuno Y. Tateishi U. Yamamoto S. Nokihara H. Yamamoto N. Sekine I. et al.J. Clin. Oncol. 2005; 23: 6829-6837Crossref PubMed Scopus (665) Google Scholar1/114 (0.8%)nonadenocarcinoma, G776ins YVMA exon 20Lee et al., 2006aLee J.W. Soung Y.H. Kim S.Y. Nam S.W. Park W.S. Wang Y.P. Jo K.H. Moon S.W. Song S.Y. Lee J.Y. et al.Cancer Lett. 2006; 237: 89-94Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar1/122 (0.8%)adenocarcinoma, G776ins YVMASasaki et al., 2006Sasaki H. Shimizu S. Endo K. Takada M. Kawahara M. Tanaka H. Matsumura A. Iuchi K. Haneda H. Suzuki E. et al.Int. J. Cancer. 2006; 118: 180-184Crossref PubMed Scopus (147) Google ScholarTotal18/1093 (1.6%)17 adenocarcinomasSCLC0/36Shigematsu et al., 2005Shigematsu H. Takahashi T. Nomura M. Majmudar K. Suzuki M. Lee H. Wistuba I.I. Fong K.M. Toyooka S. Shimizu N. et al.Cancer Res. 2005; 65: 1642-1646Crossref PubMed Scopus (555) Google ScholarGastric9/180 (5%)various mutationsLee et al., 2006bLee J.W. Soung Y.H. Seo S.H. Kim S.Y. Park C.H. Wang Y.P. Park K. Nam S.W. Park W.S. Kim S.H. et al.Clin. Cancer Res. 2006; 12: 57-61Crossref PubMed Scopus (172) Google ScholarCRC0/28Shigematsu et al., 2005Shigematsu H. Takahashi T. Nomura M. Majmudar K. Suzuki M. Lee H. Wistuba I.I. Fong K.M. Toyooka S. Shimizu N. et al.Cancer Res. 2005; 65: 1642-1646Crossref PubMed Scopus (555) Google Scholar3/104 (2.9%)all carry K-ras mutations, V777L, M; V842ILee et al., 2006bLee J.W. Soung Y.H. Seo S.H. Kim S.Y. Park C.H. Wang Y.P. Park K. Nam S.W. Park W.S. Kim S.H. et al.Clin. Cancer Res. 2006; 12: 57-61Crossref PubMed Scopus (172) Google ScholarTotal3/132 (2.3%)Breast0/28Shigematsu et al., 2005Shigematsu H. Takahashi T. Nomura M. Majmudar K. Suzuki M. Lee H. Wistuba I.I. Fong K.M. Toyooka S. Shimizu N. et al.Cancer Res. 2005; 65: 1642-1646Crossref PubMed Scopus (555) Google Scholar4/94 (4.3%)none with ErbB2 amplification, del L755-T759, L755S, P; R896CLee et al., 2006bLee J.W. Soung Y.H. Seo S.H. Kim S.Y. Park C.H. Wang Y.P. Park K. Nam S.W. Park W.S. Kim S.H. et al.Clin. Cancer Res. 2006; 12: 57-61Crossref PubMed Scopus (172) Google ScholarTotal4/122 (3.3%)SCCHN1/4 (25%)Gefitinib-responsive patient, V773ACohen et al., 2005Cohen E.E. Lingen M.W. Martin L.E. Harris P.L. Brannigan B.W. Haserlat S.M. Okimoto R.A. Sgroi D.C. Dahiya S. Muir B. et al.Clin. Cancer Res. 2005; 11: 8105-8108Crossref PubMed Scopus (118) Google ScholarBladder0/15Shigematsu et al., 2005Shigematsu H. Takahashi T. Nomura M. Majmudar K. Suzuki M. Lee H. Wistuba I.I. Fong K.M. Toyooka S. Shimizu N. et al.Cancer Res. 2005; 65: 1642-1646Crossref PubMed Scopus (555) Google ScholarProstate0/14Shigematsu et al., 2005Shigematsu H. Takahashi T. Nomura M. Majmudar K. Suzuki M. Lee H. Wistuba I.I. Fong K.M. Toyooka S. Shimizu N. et al.Cancer Res. 2005; 65: 1642-1646Crossref PubMed Scopus (555) Google ScholarOvary1/188 (0.5%)G776ins YVMA exon 20Lassus et al., 2006Lassus H. Sihto H. Leminen A. Joensuu H. Isola J. Nupponen N.N. Butzow R. J. Mol. Med. 2006; (Published online April 11, 2006)https://doi.org/10.1007/s00109-006-0054-4Crossref PubMed Scopus (115) Google Scholar Open table in a new tab The biochemical and biological consequences of EGFR mutations have been studied by various means. Most of the missense mutations and in-frame deletions that arise in exons 18–21 of the KD affect residues in the ATP binding pocket (Figure 1). Recent mutational and crystallographic studies revealed that the kinase activity of EGFRWT is autoinhibited and that this conformation is destabilized by a common mutation, L834R, conferring on the mutant a dramatic increase in basal and ligand-induced kinase activity (Zhang et al., 2006Zhang X. Gureasko J. Shen K. Cole P.A. Kuriyan J. Cell. 2006; 125: 1137-1149Abstract Full Text Full Text PDF PubMed Scopus (1065) Google Scholar). In vitro data from cellular models suggest that KD mutations enhance coupling of the mutant receptor to prosurvival pathways (Greulich et al., 2005Greulich H. Chen T.H. Feng W. Janne P.A. Alvarez J.V. Zappaterra M. Bulmer S.E. Frank D.A. Hahn W.C. Sellers W.R. Meyerson M. PLoS Med. 2005; 2: e313https://doi.org/10.1371/journal.pmed.0020313Crossref PubMed Scopus (546) Google Scholar, Sordella et al., 2004Sordella R. Bell D.W. Haber D.A. Settleman J. Science. 2004; 305: 1163-1167Crossref PubMed Scopus (1418) Google Scholar). This hypothesis is supported by the clinical observation that increased EGFR copy number was observed more frequently in patients bearing EGFR KD mutations than in patients with EGFRWT (Cappuzzo et al., 2005aCappuzzo F. Hirsch F.R. Rossi E. Bartolini S. Ceresoli G.L. Bemis L. Haney J. Witta S. Danenberg K. Domenichini I. et al.J. Natl. Cancer Inst. 2005; 97: 643-655Crossref PubMed Scopus (1450) Google Scholar), suggesting that mutant EGFR alleles are selectively amplified and required for NSCLC survival. Results from transgenic models provide convincing support for the importance of EGFR KD mutations in lung cancer (Ji et al., 2006Ji H. Li D. Chen L. Shimamura T. Kobayashi S. McNamara K. Mahmood U. Mitchell A. Sun Y. Al-Hashem R. et al.Cancer Cell. 2006; 9: 485-495Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar, Politi et al., 2006Politi K. Zakowski M.F. Fan P.D. Schonfeld E.A. Pao W. Varmus H.E. Genes Dev. 2006; 20: 1496-1510Crossref PubMed Scopus (352) Google Scholar). Inducible expression of two common EGFR mutations in transgenic animals rapidly induced lung adenocarcinomas with features similar to those seen in human tumors with EGFR KD mutations. Withdrawal of the inducer led to tumor regression in the mice, demonstrating the importance of mutant EGFR in cancer cell survival. Importantly, the mice responded to EGFR-selective TKIs, rapidly demonstrating a significant tumor reduction (Ji et al., 2006Ji H. Li D. Chen L. Shimamura T. Kobayashi S. McNamara K. Mahmood U. Mitchell A. Sun Y. Al-Hashem R. et al.Cancer Cell. 2006; 9: 485-495Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar). These mice provide excellent models for further studies on tumor biology and response. ERBB2 KD mutations were initially detected in NSCLC (Stephens et al., 2004Stephens P. Hunter C. Bignell G. Edkins S. Davies H. Teague J. Stevens C. O'Meara S. Smith R. Parker A. et al.Nature. 2004; 431: 525-526Crossref PubMed Scopus (17) Google Scholar), although at a lower frequency than EGFR mutations. However, neither the biology of mutant ERBB2 nor its impact on clinical response to TKIs has been reported. This is where the new study of Arteaga and colleagues comes into the picture (Wang et al., 2006Wang S.E. Narasanna A. Perez-Torres M. Xiang B. Wu F.Y. Yang S. Carpenter G. Gazdar A.F. Muthuswamy S.K. Arteaga C.L. Cancer Cell. 2006; (this issue)Google Scholar). The group examined the biological effects of two different ERBB2 KD mutants, the G776YVMA and G776VC insertions. Following introduction into normal human breast and lung cells, mutant ERBB2 was constitutively active and conferred oncogenic properties on the cells. Moreover, EGFR displayed elevated activity, and multiple downstream signaling pathways were stimulated. Mutant ERBB2-expressing cells were tested for their sensitivity to various ERBB inhibitors. Although these cells were resistant to the EGFR-selective TKIs gefitinib and erlotinib, they were sensitive to the dual EGFR/ERBB2 TKIs lapatinib and CI-1033, showing the dominance of mutant ERBB2 in this model. In the clinic it is not yet known if ERBB2 KD mutations confer resistance to gefitinib or erlotinib in NSCLC patients. In one small study that included four patients with ERBB2 KD mutation, none responded to gefitinib (Han et al., 2006Han S.W. Kim T.Y. Jeon Y.K. Hwang P.G. Im S.A. Lee K.H. Kim J.H. Kim D.W. Heo D.S. Kim N.K. et al.Clin. Cancer Res. 2006; 12: 2538-2544Crossref PubMed Scopus (226) Google Scholar), supporting the in vitro results presented by Arteaga and colleagues. In addition to their sensitivity to the dual ERBB TKIs, the transformed cells were also sensitive to the ERBB2-targeted monoclonal antibody trastuzumab (Wang et al., 2006Wang S.E. Narasanna A. Perez-Torres M. Xiang B. Wu F.Y. Yang S. Carpenter G. Gazdar A.F. Muthuswamy S.K. Arteaga C.L. Cancer Cell. 2006; (this issue)Google Scholar). It is well documented that breast cancers with ERBB2 amplification respond to trastuzumab (Hynes and Lane, 2005Hynes N.E. Lane H.A. Nat. Rev. Cancer. 2005; 5: 341-354Crossref PubMed Scopus (2528) Google Scholar), and data are emerging that elevated ERBB2 copy number might impact on response of NSCLC patients to ERBB-targeted therapies (Cappuzzo et al., 2005cCappuzzo F. Varella-Garcia M. Shigematsu H. Domenichini I. Bartolini S. Ceresoli G.L. Rossi E. Ludovini V. Gregorc V. Toschi L. et al.J. Clin. Oncol. 2005; 23: 5007-5018Crossref PubMed Scopus (338) Google Scholar). ERBB2 amplification is found in 11% of NSCLC specimens (discussed in Rosell, 2004Rosell R. J. Clin. Oncol. 2004; 22: 1171-1173Crossref PubMed Scopus (19) Google Scholar), and results from clinical trials suggest that the subgroup of patients with amplification achieve clinical benefit when trastuzumab is added to different chemotherapy regimes (Langer et al., 2004Langer C.J. Stephenson P. Thor A. Vangel M. Johnson D.H. J. Clin. Oncol. 2004; 22: 1180-1187Crossref PubMed Scopus (174) Google Scholar). Intriguingly, it was recently reported that trastuzumab in combination with paclitaxel led to a partial response of a NSCLC patient with increased ERBB2 copy number and an ERBB2 KD mutation (G776L) (Cappuzzo et al., 2006Cappuzzo F. Bemis L. Varella-Garcia M. N. Engl. J. Med. 2006; 354: 2619-2621Crossref PubMed Scopus (183) Google Scholar). Although currently based on one example, it is possible that screening for ERBB2 amplification in combination with mutation will be the ultimate test for choosing NSCLC patients who might be considered for trastuzumab therapy. Based upon the results reported by Wang et al., 2006Wang S.E. Narasanna A. Perez-Torres M. Xiang B. Wu F.Y. Yang S. Carpenter G. Gazdar A.F. Muthuswamy S.K. Arteaga C.L. Cancer Cell. 2006; (this issue)Google Scholar, these patients might also respond to a dual EGFR/ERBB2 inhibitor. There is emerging evidence that ERBB3 and ERBB4 also have roles in common human cancers. ERBB4 KD mutations have been detected in 2.0% of tumor tissues (n = 594), including 2.3% of NSCLCs (n = 217) (Soung et al., 2006Soung Y.H. Lee J.W. Kim S.Y. Wang Y.P. Jo K.H. Moon S.W. Park W.S. Nam S.W. Lee J.Y. Yoo N.J. Lee S.H. Int. J. Cancer. 2006; 118: 1426-1429Crossref PubMed Scopus (99) Google Scholar). Neither their impact on response to ERBB TKIs nor their biology has been studied. Genomic gain of ERBB3 does not appear to be a marker for response to TKI therapy in NSCLC (Cappuzzo et al., 2005bCappuzzo F. Toschi L. Domenichini I. Bartolini S. Ceresoli G.L. Rossi E. Ludovini V. Cancellieri A. Magrini E. Bemis L. et al.Br. J. Cancer. 2005; 93: 1334-1340Crossref PubMed Scopus (72) Google Scholar), which is not surprising since this kinase-impaired receptor acquires signaling activity only as a heterodimer with another ERBB (Hynes and Lane, 2005Hynes N.E. Lane H.A. Nat. Rev. Cancer. 2005; 5: 341-354Crossref PubMed Scopus (2528) Google Scholar). However, there are data suggesting that lung cancers that depend upon EGFR for survival activate ERBB3 via upregulation of EGF-related peptides (Fujimoto et al., 2005Fujimoto N. Wislez M. Zhang J. Iwanaga K. Dackor J. Hanna A.E. Kalyankrishna S. Cody D.D. Price R.E. Sato M. et al.Cancer Res. 2005; 65: 11478-11485Crossref PubMed Scopus (129) Google Scholar). Although ERBB3 is kinase impaired, its ability to strongly couple to PI3K confers a special role on this receptor. Cancer cells driven by ERBB2 (Holbro et al., 2003Holbro T. Beerli R.R. Maurer F. Koziczak M. Barbas III, C.F. Hynes N.E. Proc. Natl. Acad. Sci. USA. 2003; 100: 8933-8938Crossref PubMed Scopus (716) Google Scholar) or EGFR (Engelman et al., 2005Engelman J.A. Janne P.A. Mermel C. Pearlberg J. Mukohara T. Fleet C. Cichowski K. Johnson B.E. Cantley L.C. Proc. Natl. Acad. Sci. USA. 2005; 102: 3788-3793Crossref PubMed Scopus (426) Google Scholar) coopt ERBB3 to activate the PI3K/AKT pathway. In summary, an assessment of ERBB3 levels combined with ERBB2 copy number and/or mutation status in NSCLC may also prove useful for predicting response to ERBB-targeted TKIs. Resistance to ERBB inhibitors, both TKIs and antibodies, has emerged as a significant clinical problem. Resistance may be de novo, for example, in those NSCLC patients with EGFR KD mutations who never responded to TKIs. Or it is acquired, as seen in some cases where tumors arising during gefitinib or erlotinib therapy contained a secondary mutation, T790M (Kobayashi et al., 2005Kobayashi S. Boggon T.J. Dayaram T. Janne P.A. Kocher O. Meyerson M. Johnson B.E. Eck M.J. Tenen D.G. Halmos B. N. Engl. J. Med. 2005; 352: 786-792Crossref PubMed Scopus (3220) Google Scholar, Pao et al., 2005Pao W. Miller V.A. Politi K.A. Riely G.J. Somwar R. Zakowski M.F. Kris M.G. Varmus H. PLoS Med. 2005; 2: e73https://doi.org/10.1371/journal.pmed.0020073Crossref PubMed Scopus (2904) Google Scholar). Based upon the model of erlotinib bound to the KD of EGFR, the change at residue 790 is predicted to keep the receptor active but prevent the TKI from binding (Kobayashi et al., 2005Kobayashi S. Boggon T.J. Dayaram T. Janne P.A. Kocher O. Meyerson M. Johnson B.E. Eck M.J. Tenen D.G. Halmos B. N. Engl. J. Med. 2005; 352: 786-792Crossref PubMed Scopus (3220) Google Scholar). Fortunately, this class of TKI-resistant mutants is sensitive to other EGFR inhibitors, such as CL-387,785 (Greulich et al., 2005Greulich H. Chen T.H. Feng W. Janne P.A. Alvarez J.V. Zappaterra M. Bulmer S.E. Frank D.A. Hahn W.C. Sellers W.R. Meyerson M. PLoS Med. 2005; 2: e313https://doi.org/10.1371/journal.pmed.0020313Crossref PubMed Scopus (546) Google Scholar). Acquired resistance also results from alterations in EGFR trafficking (Kwak et al., 2005Kwak E.L. Sordella R. Bell D.W. Godin-Heymann N. Okimoto R.A. Brannigan B.W. Harris P.L. Driscoll D.R. Fidias P. Lynch T.J. et al.Proc. Natl. Acad. Sci. USA. 2005; 102: 7665-7670Crossref PubMed Scopus (826) Google Scholar), a process that is subject to multiple control mechanisms (Lenferink et al., 1998Lenferink A.E. Pinkas-Kramarski R. van de Poll M.L. van Vugt M.J. Klapper L.N. Tzahar E. Waterman H. Sela M. van Zoelen E.J. Yarden Y. EMBO J. 1998; 17: 3385-3397Crossref PubMed Scopus (326) Google Scholar) and plays an important role in receptor signaling activity (Wiley, 2003Wiley H.S. Exp. Cell Res. 2003; 284: 78-88Crossref PubMed Scopus (291) Google Scholar). In a NSCLC cell line model of acquired gefitinib resistance, EGFR internalization was more rapid in the resistant than in the parental cells (Kwak et al., 2005Kwak E.L. Sordella R. Bell D.W. Godin-Heymann N. Okimoto R.A. Brannigan B.W. Harris P.L. Driscoll D.R. Fidias P. Lynch T.J. et al.Proc. Natl. Acad. Sci. USA. 2005; 102: 7665-7670Crossref PubMed Scopus (826) Google Scholar). Importantly, the gefitinib-resistant cells remained sensitive to irreversible ERBB-selective TKIs (Kwak et al., 2005Kwak E.L. Sordella R. Bell D.W. Godin-Heymann N. Okimoto R.A. Brannigan B.W. Harris P.L. Driscoll D.R. Fidias P. Lynch T.J. et al.Proc. Natl. Acad. Sci. USA. 2005; 102: 7665-7670Crossref PubMed Scopus (826) Google Scholar). These results suggest that intracellular dissociation of reversible ERBB inhibitors may play a role in resistance and that an irreversible TKI might not be subject to this effect. In fact, differences in EGFR trafficking in cancer cells might have a general role in TKI response, and it will be interesting to develop additional in vitro models for testing this. The paper by Zhou and colleagues presents evidence for another resistance mechanism in NSCLC, one that involves autocrine ligand production (Zhou et al., 2006Zhou B.-B.S. Peyton M. He B. Liu C. Girard L. Caudler E. Lo Y. Baribaud F. Mikami I. Reguart N. et al.Cancer Cell. 2006; (this issue)Google Scholar). The EGF-related peptides are synthesized as transmembrane precursors that are cleaved by cell surface proteases (Harris et al., 2003Harris R.C. Chung E. Coffey R.J. Exp. Cell Res. 2003; 284: 2-13Crossref PubMed Scopus (572) Google Scholar), leading to the release of soluble ligands. This cleavage is an important step in the control of ligand availability and receptor activation (Borrell-Pages et al., 2003Borrell-Pages M. Rojo F. Albanell J. Baselga J. Arribas J. EMBO J. 2003; 22: 1114-1124Crossref PubMed Scopus (233) Google Scholar). The ADAMs (a disintegrin and metalloproteases), zinc-dependent membrane-associated proteases, control the cleavage of most EGF-related ligands (Blobel, 2005Blobel C.P. Nat. Rev. Mol. Cell Biol. 2005; 6: 32-43Crossref PubMed Scopus (853) Google Scholar). The ADAMs family has 29 mammalian members that share a common molecular structure. Catalytically active ADAMs cleave a variety of substrates, including growth factors and extracellular matrix proteins (Blobel, 2005Blobel C.P. Nat. Rev. Mol. Cell Biol. 2005; 6: 32-43Crossref PubMed Scopus (853) Google Scholar, Seals and Courtneidge, 2003Seals D.F. Courtneidge S.A. Genes Dev. 2003; 17: 7-30Crossref PubMed Scopus (843) Google Scholar, Zhou et al., 2005Zhou B.B. Fridman J.S. Liu X. Friedman S.M. Newton R.C. Scherle P.A. Expert Opin. Investig. Drugs. 2005; 14: 591-606Crossref PubMed Scopus (22) Google Scholar). Various lines of evidence suggest that ADAM10 and ADAM17 are the principle proteases for the ERBB ligands (Sahin et al., 2004Sahin U. Weskamp G. Kelly K. Zhou H.M. Higashiyama S. Peschon J. Hartmann D. Saftig P. Blobel C.P. J. Cell Biol. 2004; 164: 769-779Crossref PubMed Scopus (735) Google Scholar). Zhou and colleagues provide evidence suggesting that HRG-mediated ERBB3 activation might be an important gefitinib resistance mechanism. An examination of primary NSCLC tissues revealed that most expressed HRG and ERBB3; active ERBB3 was found in a subset. Since NSCLCs also express EGFR and ERBB2, they hypothesized that autocrine HRG activation of ERBB3-containing heterodimers might prevent gefitinib response, since these heterodimers are unlikely to respond to the EGFR-selective TKI. This was tested using NSCLC cell lines, where they showed that gefitinib insensitivity significantly correlated with HRG expression. Based upon ADAM17 overexpression in tumors with ERBB3 activity, and the role of ADAM10 and ADAM17 in ERBB ligand cleavage, they identified INCB3619, a small molecule that strongly inhibits both ADAMs. Importantly, this dual ADAM inhibitor blocked HRG release in a gefitinib-resistant NSCLC cell line, sensitizing the tumor cells to the TKI. These are exciting results, since ADAM10 has also been implicated in autocrine EGFR activity in breast cancer (Borrell-Pages et al., 2003Borrell-Pages M. Rojo F. Albanell J. Baselga J. Arribas J. EMBO J. 2003; 22: 1114-1124Crossref PubMed Scopus (233) Google Scholar; see Table 2 for other ADAMs implicated in cancer). Furthermore, in ERBB2-positive breast cancer, autocrine ligand production might also interfere with trastuzumab response, since trastuzumab-sensitive breast tumor cell lines become resistant to the antibody in the presence of EGF-related ligands (Motoyama et al., 2002Motoyama A.B. Hynes N.E. Lane H.A. Cancer Res. 2002; 62: 3151-3158PubMed Google Scholar). Trastuzumab binds domain IV of ERBB2, a region not involved in receptor 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. Nature. 2003; 421: 756-760Crossref PubMed Scopus (1083) Google Scholar), which explains why ERBB ligands can induce activation of ERBB2-containing dimers in the presence of the antibody. At this point one might ask whether a dual EGFR/ERBB2 inhibitor that should also block HRG-induced ERBB2/ERBB3 heterodimers might be sufficient to overcome HRG-mediated resistance, making combined inhibition of ERBBs and ADAMs superfluous. Since Zhou and colleagues only examined sensitivity of NSCLC cell lines to gefitinib, these data are not available. However, it should be kept in mind that ADAMs have many substrates whose processing might circumvent ERBB inhibition by other mechanisms. In fact, ADAMs cleave the ectodomain of ERBB2, leaving behind an active truncated receptor (Molina et al., 2001Molina M.A. Codony-Servat J. Albanell J. Rojo F. Arribas J. Baselga J. Cancer Res. 2001; 61: 4744-4749PubMed Google Scholar). Furthermore, ADAM-mediated proteolysis of IGFBPs (discussed in Zhou et al., 2005Zhou B.B. Fridman J.S. Liu X. Friedman S.M. Newton R.C. Scherle P.A. Expert Opin. Investig. Drugs. 2005; 14: 591-606Crossref PubMed Scopus (22) Google Scholar) releases IGF-1, a peptide known to play a role in circumventing ERBB inhibitors (Lu et al., 2001Lu Y. Zi X. Zhao Y. Mascarenhas D. Pollak M. J. Natl. Cancer Inst. 2001; 93: 1852-1857Crossref PubMed Scopus (744) Google Scholar). In summary, information from the new papers in this issue of Cancer Cell suggest that dual EGFR/ERBB2 inhibitors either alone or combined with a selective ADAM inhibitor might be effective in cancers with autocrine ligand activation of ERBB receptors and ERBB KD mutations.Table 2ADAMs, ERBB ligand shedding, and potential roles in different cancer typesADAMShedding of ERBB ligandsExpression in cancerReferenceADAM8?RCC, NSCLC, brainRocks et al., 2006Rocks N. Paulissen G. Quesada Calvo F. Polette M. Gueders M. Munaut C. Foidart J.M. Noel A. Birembaut P. Cataldo D. Br. J. Cancer. 2006; 94: 724-730Crossref PubMed Scopus (75) Google ScholarADAM9HB-EGFmyeloma, breast, gastric, prostate, NSCLC, melanoma, HCCSahin et al., 2004Sahin U. Weskamp G. Kelly K. Zhou H.M. Higashiyama S. Peschon J. Hartmann D. Saftig P. Blobel C.P. J. Cell Biol. 2004; 164: 769-779Crossref PubMed Scopus (735) Google ScholarADAM10HB-EGF, EGF, BTCbreast, CRC, uterus, ovary, prostate, hematological malignancies, gastricSahin et al., 2004Sahin U. Weskamp G. Kelly K. Zhou H.M. Higashiyama S. Peschon J. Hartmann D. Saftig P. Blobel C.P. J. Cell Biol. 2004; 164: 769-779Crossref PubMed Scopus (735) Google ScholarADAM12HB-EGFbreast, gastric, glioblastoma, hematological malignancies, liver, colonAsakura et al., 2002Asakura M. Kitakaze M. Takashima S. Liao Y. Ishikura F. Yoshinaka T. Ohmoto H. Node K. Yoshino K. Ishiguro H. et al.Nat. Med. 2002; 8: 35-40Crossref PubMed Scopus (631) Google ScholarADAM15HB-EGF, AR, TGFαbreast, hematological malignancies, gastric, prostate, lung carcinomaHart et al., 2005Hart S. Fischer O.M. Prenzel N. Zwick-Wallasch E. Schneider M. Hennighausen L. Ullrich A. Biol. Chem. 2005; 386: 845-855Crossref PubMed Scopus (83) Google ScholarADAM17HB-EGF, AR, TGFα, EPR, NRGα2c, -β1, -β2breast, prostate, gastric, CRC, HCC, ovary, RCCHoriuchi et al., 2005Horiuchi K. Zhou H.M. Kelly K. Manova K. Blobel C.P. Dev. Biol. 2005; 283: 459-471Crossref PubMed Scopus (134) Google ScholarADAM19NRGβ1, -4brain, RCCWildeboer et al., 2006Wildeboer D. Naus S. Amy Sang Q.X. Bartsch J.W. Pagenstecher A. J. Neuropathol. Exp. Neurol. 2006; 65: 516-527Crossref PubMed Scopus (116) Google ScholarADAM28?NSCLCOhtsuka et al., 2006Ohtsuka T. Shiomi T. Shimoda M. Kodama T. Amour A. Murphy G. Ohuchi E. Kobayashi K. Okada Y. Int. J. Cancer. 2006; 118: 263-273Crossref PubMed Scopus (80) Google Scholar Open table in a new tab The authors are supported by a grant from Onco Suisse (01445-12-2003) and by the Novartis Forschungsstiftung Zweigniederlassung Friedrich Miescher Institute for Biomedical Research. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitorsWang et al.Cancer CellJuly, 2006In BriefHER2/Neu gene mutations have been identified in lung cancer. Expression of a HER2 mutant containing a G776YVMA insertion in exon 20 was more potent than wild-type HER2 in associating with and activating signal transducers, phosphorylating EGFR, and inducing survival, invasiveness, and tumorigenicity. HER2YVMA transphosphorylated kinase-dead EGFRK721R and EGFRWT in the presence of EGFR tyrosine kinase inhibitors (TKIs). Knockdown of mutant HER2 in H1781 lung cancer cells increased apoptosis and restored sensitivity to EGFR TKIs. Full-Text PDF Open ArchiveTargeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancerZhou et al.Cancer CellJuly, 2006In BriefWe describe here the existence of a heregulin-HER3 autocrine loop, and the contribution of heregulin-dependent, HER2-mediated HER3 activation to gefitinib insensitivity in non-small cell lung cancer (NSCLC). ADAM17 protein, a major ErbB ligand sheddase, is upregulated in NSCLC and is required not only for heregulin-dependent HER3 signaling, but also for EGFR ligand-dependent signaling in NSCLC cell lines. A selective ADAM inhibitor, INCB3619, prevents the processing and activation of multiple ErbB ligands, including heregulin. Full-Text PDF Open Archive
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