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The Epidermal Growth Factor Receptor Pathway: A Model for Targeted Therapy

Authors' Affiliations: ¹ Medical Oncology Service, Vall d'Hebron University Hospital and Universidad Autónoma de Barcelona, Barcelona, Spain and ² Dipartimento di Medicina Sperimentale, Universita' degli Studi di Parma, Parma, Italy

Requests for reprints: José Baselga, Medical Oncology Service, Vall d'Hebron University Hospital, P. Vall d'Hebron 119-129, Barcelona 08035, Spain. Phone: 34-93-274-6077; Fax: 34-93-274-6059; E-mail: jbaselga{at}vhebron.net.

	Abstract

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The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase receptor that is frequently expressed in epithelial tumors. The EGFR was the first receptor to be proposed as a target for cancer therapy, and after 2 decades of intensive research, there are several anti-EGFR agents available in the clinic. Recent advances in our understanding in the mechanisms of receptor activation and function, discovery of primary and secondary EGFR somatic mutations, as well as a new generation of anti-EGFR agents provide new leads on the clinical targeting of this receptor and may serve as a model for strategies aimed at targeting other receptors.

	Background

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EGFR becomes activated by receptor overexpression (frequent in cancer) as well as ligand-dependent and ligand-independent mechanisms. There are six known ligands that bind to the EGFR, including EGF itself and transforming growth factor-. Ligand binding to the receptor induces a conformational change of the receptor ectodomain that allows for receptor dimerization and autophosphorylation of several tyrosine residues within the COOH-terminal tail of the receptors (3, 4).

Ligand-independent receptor activation occurs in some tumors that display forms of the EGFR and HER that have a deletion of the extracellular domain that result in constitutive receptor activation (5, 6). Overexpression of the urokinase-type plasminogen activator receptor also results in ligand-independent activation of the EFGR via association ₅ß₁ integrin (7). Finally, ligand-independent receptor activation occurs as a result of cellular stresses, such as radiation, which silence phosphatases that antagonize the receptor kinase activity, thereby shifting the equilibrium of basal phosphorylation toward the activated state (8).

Activation of the receptor leads to the phosphorylation of key tyrosine residues within the COOH-terminal portion of EGFR and, as a result, provides specific docking sites for cytoplasmic proteins containing Src homology 2 and phosphotyrosine-binding domains (1). These proteins bind to specific phosphotyrosine residues and initiate intracellular signaling via several pathways (Fig. 1 ).

View larger version (72K): [in this window] [in a new window]   Fig. 1. Signaling pathways and inhibitors of EGFR. Activation of EGFR leads to homodimerization/heterodimerization, phosphorylation of specific tyrosine residues, and recruitment of several proteins at the intracellular portion of the receptors. Phospholipase C (pink) and STAT transcription factors (blue) bind directly to the receptor, whereas Ras/Raf/MAPK pathway (orange) and PI3K pathway (green) need several specific adaptor molecules (yellow). PI3K can also bind directly any of the erbB partners of EGFR heterodimers. Concomitantly, the activated receptors undergo endocytosis and follow two possible routes: lysosomal degradation or importin-mediated nuclear translocation. Once in the nucleus, EGFR can either behave as a proper transcription factor (for cyclin D1 up-regulation) or as coregulator of other gene transactivators. Both pathways result in nuclear activation of genes related with cell proliferation, survival, invasion, and metastasis. Two main strategies are available for EGFR kinase inhibition: mAb and small-molecule TKIs. mAbs act extracellularly, avoiding EGFR ligands binding, whereas TKIs compete with the ATP binding to the kinase domain of the receptor. DAG, 1,2-diacylglycerol; IP3, inositol 1,3,5-triphosphate; PLC, phospholipase C; Erk-1, extracellular signal-regulated kinase-1; Erk-2, extracellular signal-regulated kinase-2; FAK, focal adhesion kinase; PKC, protein kinase C.

Phosphatidylinositol 3-kinase/Akt pathway. This pathway is involved in cell growth, apoptosis resistance, invasion, and migration (see refs. 15, 16 for review). Phosphatidylinositol 3-kinase (PI3K) is a dimeric enzyme composed of a regulatory p85 subunit, responsible of the anchorage to erbB receptor-specific docking sites, and a catalytic p110 subunit that generates the second messenger phosphatidylinositol 3,4,5-triphosphate, which is responsible for phosphorylation and activation of the protein serine/threonine kinase Akt (15). The principal mechanism that drives EGFR-dependent PI3K activation is the dimerization of the receptor with HER-3. In fact, docking sites for p85 are absent on EGFR, whereas, on the contrary, docking sites for p85 are abundant on HER-3 (17, 18). Alternatively, the p85 subunit can interact with EGFR through the docking protein Gab-1 (19).

Phospholipase C. Phospholipase C interacts directly with activated EGFR and hydrolyses phosphatidylinositol 4,5-diphosphate to give inositol 1,3,5-triphosphate, important for intracellular calcium release, and 1,2-diacylglycerol, cofactor in protein kinase C activation (20, 21). Protein kinase C activation can, in turn, result in MAPK and c-Jun NH₂-terminal kinase activation (22, 23).

Signal transducers and activators of transcription pathway. Signal transducers and activators of transcription (STAT) proteins interact with phosphotyrosine residues via their Src homology 2 domains and, on dimerization, translocate to the nucleus and drive the expression of specific target genes (24). Constitutive activation of STAT proteins and especially STAT3 has been found in numerous primary cancers and tumor-derived cell lines (25). Augmented activity of membrane-associated tyrosine kinases, such as EGFR, HER-2, and platelet-derived growth factor receptor, promotes STAT3 persistent activation, which contribute to oncogenesis or tumor progression (25).

Src kinase pathways. Src is the archetypal member of a nine-gene family of nonreceptor tyrosine kinases that plays a critical role in the regulation in cell proliferation, migration, adhesion, angiogenesis, and immune function (26, 27). Src, which is located in the cytosol, activates a series of substrates, including focal adhesion kinase, PI3K, and STAT proteins (26, 27). Although Src functions independently, it also cooperates with other receptor tyrosine kinases signaling. The interaction between EGFR and Src is complex. On one hand, Src serves as a signal transducer and an enhancer of EGFR activation (28, 29). On the other, it may be involved in resistance to EGFR therapies via independent activation or association with other receptors.

	Recent Advances

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The initial proposal for targeting the EGFR in cancer was mostly based on the observation that the receptor was frequently overexpressed in epithelial tumors and on the preclinical activity of anti-EGFR monoclonal antibodies (mAb; ref. 30). In the last few years, the oncogenic role of the EGFR has been more finely characterized due to an improved understanding of the mechanisms of receptor activation, the finding of somatic mutations of the receptor as well as mutations in components of the signaling pathway of the receptor, and in great measure due to the clinical success of anti-EGFR therapies in the clinic.

New insights into mechanisms of receptor activation and function. Over the last few years, a substantial amount of structural data has illuminated the mechanisms governing ligand-mediated activation of the EGFR. Ligand binding to the receptor ectodomain creates an extended and stabilized conformation of the entire ectodomain, which promotes homodimerization and heterodimerization (see refs. 3, 4 for reviews). mAbs prevent the receptor from adopting this extended and stabilized conformation required for dimerization due to steric clashes between the Fab domain of the antibody and one of the domains of the extracellular portion of the receptor. This mechanism of action could be important in situations in which activation of the receptor occurs via stabilization of the extended configuration in the absence of ligand binding, which is felt to occur under conditions of high receptor expression. Although ligand-induced conformational changes of the receptor explain ligand-induced dimerization, the mechanism by which the EGFR is activated on dimerization has not been well understood. In an important recent contribution, it has been shown that, in basal conditions, the EGFR kinase domain remains in an autoinhibited conformation similar to that of Src and cyclin-dependent kinases (31). EGFR activation results from the formation of an asymmetrical dimer in which the COOH-terminal lobe of one kinase domain plays a role analogous to that of cyclin in activated cyclin-dependent kinase/cyclin complexes (31).

There is also increasing evidence that the EGFR family of receptors has the ability to translocate to the nucleus where it may exert a variety of biological actions. Members of this receptor family that have been found in the nucleus include HER-2 (32), HER-3 (33, 34), the truncated COOH-terminal portion of HER-4 (35), and, more recently, a truncated constitutively active form of HER-2 (6). For EGFR, part of the receptors may escape the internalization and lysosomal degradation route and translocate in the nucleus, where it functions as a transcription factor of the cyclin D1 gene (36) or behaves like a cofactor of STAT3 and E2F1 transcription factors (37, 38). The functional implications of EGFR localization in the nucleus are unknown but nuclear EGFR may correlate with a decreased overall survival in patients with breast cancer (39). The therapeutic implications of localization of the receptor in the nucleus are that it may result in resistance to the growth-inhibitory effects of mAbs (6).

Somatic mutations of the EGFR and downstream signaling molecules. Recently, several somatic mutations in the EGFR gene have been found to be closely linked with favorable response to the anti-EGFR tyrosine kinase inhibitors (TKI) gefitinib and erlotinib in non–small cell lung cancer patients (40, 41). The mutations arise in four exons within the kinase domain of the receptor: point mutation of G719 in the exon 18, deletion of the amino acids 747 to 750 in the exon 19, in-frame insertions in the exon 20, and point mutations of L858 and L861 in the exon 21. These mutations arise more frequently in a subpopulation of non–small cell lung cancer patients: women, Japanese, and nonsmokers with bronchioalveolar adenocarcinoma histology (42).

It is important to realize that the clinical benefit observed with anti-EGFR TKIs is not restricted to those patients harboring EGFR gene mutations. There is also a strong correlation between EGFR gene amplification and a high response to EGFR TKIs and tumors that, with EGFR amplification, have frequently coexisting EGFR mutations (43). On the other hand, the presence of K-RAS mutations, frequent in smokers, correlates with resistance to EGFR inhibitors (44). In a similar fashion as with EGFR, HER-2 mutations have been observed in lung adenocarcinomas (45). Another potential molecular predictor of response to EGFR TKIs is expression of erbB3, expressed in high levels in gefitinib-sensitive non–small cell lung cancer cell lines and in patients that achieve clinical benefit from gefitinib (46).

Genome sequencing approaches have identified additional activating mutations in components of the EGFR receptor signaling pathway. These include, in addition to the RAS mutations mentioned above, B-Raf mutations in melanoma (47) and somatic mutations in the PI3KCA gene, which encodes the p110 catalytic subunit of PI3K, in a variable cohort of colon, brain, gastric, breast, and lung cancers (48). These findings are of considerable importance, as B-Raf mutant tumors are exquisitely sensitive to small-molecule MAPK/extracellular signal-regulated kinase kinase inhibitors (49). Loss of function of PTEN, a tumor suppressor phosphatase gene that selectively dephosphorylates phosphatidylinositol 3,4,5-triphosphate, has been found in a wide group of cancers (50) and results in increased PI3K activity and overdependence on this pathway, as PTEN-null cells exhibit supersensitivity to mammalian target of rapamycin (downstream of Akt) and PI3K inhibitors (51). The potential therapeutic implications of these mutations are substantial, and clinical trials with MAPK/extracellular signal-regulated kinase kinase and PI3K inhibitors are under way.

Acquired resistance to anti-EGFR agents due to secondary mutations. Patients who initially respond to gefitinib or erlotinib may acquire secondary EGFR mutations, specifically the T790M mutation (52, 53). Interestingly, a series of irreversible EGFR inhibitors have shown to be active at blocking receptor signaling and inhibiting growth in tumor cells harboring the T790M mutation (54). Clinical studies with these agents are ongoing in patients with lung cancer that have progressed to erlotinib.

	Clinical-Translational Advances

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There are two classes of anti-EGFR agents that have shown clinical activity and achieved regulatory approval for the treatment of cancer. These are mAbs directed at the extracellular domain of the receptor and low molecular weight, ATP-competitive inhibitors of the tyrosine kinase of the receptor (TKIs; reviewed in ref. 55). Anti-EGFR mAbs have now been approved for the treatment of advanced colorectal and head and neck tumors, and EGFR TKIs have been approved for the treatment of advanced non–small cell lung cancer and pancreatic carcinoma. Of note, EGFR TKIs have also activity in head and neck tumors and in glioblastoma.

An important challenge is the identification of EGFR-dependent tumors that may therefore be sensitive to EGFR inhibitors. Several tumor biopsy-driven clinical trials have shown that, at EGFR, inhibitors given at full doses successfully prevent receptor activation in the vast majority of cases and that receptor inhibition does not correlate with clinical benefit (56, 57). Hence, inhibition of receptor activation may be required but is not enough to achieve clinical benefit with anti-EGFR. As mentioned above, in non–small cell lung cancer, the presence of somatic EGFR mutations and/or EGFR gene amplification predicts for a higher response rate but mutations have not been identified in other tumor types that benefit from EGFR therapies (58). Therefore, in addition to looking at specific EGFR gene mutations, alternative approaches, such as gene expression signatures, could also reflect the activation status of several oncogenic pathways (59) and there are several ongoing studies that are incorporating this approach.

It would also be most useful to incorporate on-study assessments of biomarkers of drug sensitivity in tumors. For example, in transgenic mice expressing a mutant EGFR under transcriptional control develop lung carcinomas. On reduced expression of the transgene or, as a result, treatment with EGFR inhibitors, tumor regression was observed due to enhanced apoptosis (60). Enhanced apoptosis has also been in patients with lung cancer treated with EGFR inhibitors (61). Therefore, window trials before surgery could establish if apoptosis would be a marker of EGFR dependency.

Finally, the majority of EGFR-expressing tumors have a complex genetic background and there is a significant level of compensatory ‘cross-talk’ among receptors within a signaling network as well as with other pathways regulating cell proliferation, trafficking, and survival. As with conventional chemotherapeutic agents, rationally developed biologically and molecularly targeted combinations are going to be likely to enhance the contribution of these agents to the treatment of cancer.

	Footnotes

 
Grant support: Spanish Science and Technology Ministry grant SAF2003-03818 and Breast Cancer Research Foundation grant.

Received 6/26/06; revised 7/20/06; accepted 7/21/06.

	References

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1. Yarden Y, Sliwkowski M. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127–37.[CrossRef][Medline]
2. Hynes NE, Lane HA. ErbB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5:341.[CrossRef][Medline]
3. Burgess AW, Cho HS, Eigenbrot C, et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell 2003;12:541–52.[CrossRef][Medline]
4. Hubbard SR. EGF receptor inhibition: attacks on multiple fronts. Cancer Cell 2005;7:287–8.[CrossRef][Medline]
5. Frederick L, Wang XY, Eley G, James CD. Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 2000;60:1383–7.[Abstract/Free Full Text]
6. Anido J, Scaltriti M, Bech Serra JJ, et al. Biosynthesis of tumorigenic HER2 C-terminal fragments by alternative initiation of translation. EMBO J 2006;25:3234–44.[CrossRef][Medline]
7. Liu D, Ghiso JA, Estrada Y, Ossowski L. EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell 2002;1:445–57.[CrossRef][Medline]
8. Fischer OM, Hart S, Gschwind A, Ullrich A. EGFR signal transactivation in cancer cells. Biochem Soc Trans 2003;31:1203–8.[Medline]
9. Lowenstein EJ, Daly RJ, Batzer AG, et al. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 1992;70:431–42.[CrossRef][Medline]
10. Batzer AG, Rotin D, Urena JM, Skolnik EY, Schlessinger J. Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor. Mol Cell Biol 1994;14:5192–201.[Abstract/Free Full Text]
11. Hallberg B, Rayter SI, Downward J. Interaction of Ras and Raf in intact mammalian cells upon extracellular stimulation. J Biol Chem 1994;269:3913–6.[Abstract/Free Full Text]
12. Liebmann C. Regulation of MAP kinase activity by peptide receptor signalling pathway: paradigms of multiplicity. Cell Signal 2001;13:777–85.[CrossRef][Medline]
13. Gaestel M. MAPKAP kinases—MKs—two's company, three's a crowd. Nat Rev Mol Cell Biol 2006;7:120–30.[CrossRef][Medline]
14. Hill CS, Treisman R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell 1995;80:199–211.[CrossRef][Medline]
15. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489–501.[CrossRef][Medline]
16. Shaw RJ, Cantley LC. Ras, PI(3)K, and mTOR signalling controls tumour cell growth. Nature 2006;441:424–30.[CrossRef][Medline]
17. Carpenter CL, Auger KR, Chanudhuri M, et al. Phosphoinositide 3-kinase is activated by phosphopeptides that bind to the SH2 domains of the 85-kDa subunit. J Biol Chem 1993;268:9478–83.[Abstract/Free Full Text]
18. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127–37.[CrossRef][Medline]
19. Mattoon DR, Lamothe B, Lax I, Schlessinger J. The docking protein Gab1 is the primary mediator of EGF-stimulated activation of the PI-3K/Akt cell survival pathway. BMC Biol 2004;2:24.[CrossRef][Medline]
20. Patterson RL, van Rossum DB, Nikolaidis N, Gill DL, Snyder SH. Phospholipase C-: diverse roles in receptor-mediated calcium signaling. Trends Biochem Sci 2005;30:688–97.[CrossRef][Medline]
21. Chattopadhyay A, Vecchi M, Ji Q, Mernaugh R, Carpenter G. The role of individual SH2 domains in mediating association of phospholipase C-1 with the activated EGF receptor. J Biol Chem 1999;274:26091–7.[Abstract/Free Full Text]
22. Schonwasser DC, Marais RM, Marshall CJ, Parker PJ. Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol Cell Biol 1998;18:790–8.[Abstract/Free Full Text]
23. McClellan M, Kievit P, Auersperg N, Rodland K. Regulation of proliferation and apoptosis by epidermal growth factor and protein kinase C in human ovarian surface epithelial cells. Exp Cell Res 1999;246:471–9.[CrossRef][Medline]
24. Haura EB, Turkson J, Jove R. Mechanisms of disease: insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol 2005;2:315–24.[CrossRef][Medline]
25. Bromberg J. Stat proteins and oncogenesis. J Clin Invest 2002;109:1139–42.[CrossRef][Medline]
26. Yeatman TJ. A renaissance for SRC. Nat Rev Cancer 2004;4:470–80.[CrossRef][Medline]
27. Summy JM, Gallick GE. Treatment for advanced tumors: SRC reclaims center stage. Clin Cancer Res 2006;12:1398–401.[Free Full Text]
28. Leu TH, Maa MC. Functional implication of the interaction between EGF receptor and c-Src. Front Biosci 2003;8:s28–38.[Medline]
29. Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 2003;284:31–53.[CrossRef][Medline]
30. Mendelsohn J. Epidermal growth factor receptor inhibition by a monoclonal antibody as anticancer therapy. Clin Cancer Res 1997;3:2703–7.[Abstract]
31. Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 2006;125:1137–49.[CrossRef][Medline]
32. Giri DK, Ali-Seyed M, Li LY, et al. Endosomal transport of ErbB-2: mechanism for nuclear entry of the cell surface receptor. Mol Cell Biol 2005;25:11005–18.[Abstract/Free Full Text]
33. Offterdinger M, Schofer C, Weipoltshammer K, Grunt TW. c-erbB-3: a nuclear protein in mammary epithelial cells. J Cell Biol 2002;157:929–39.[Abstract/Free Full Text]
34. Koumakpayi IH, Diallo JS, Le Page C, et al. Expression and nuclear localization of ErbB3 in prostate cancer. Clin Cancer Res 2006;12:2730–7.[Abstract/Free Full Text]
35. Ni CY, Murphy MP, Golde TE, Carpenter G. -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 2001;294:2179–81.[Abstract/Free Full Text]
36. Lin SY, Makino K, Xia W, et al. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat Cell Biol 2001;3:802–8.[CrossRef][Medline]
37. Lo HW, Hsu SC, Ali-Seyed M, et al. Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. Cancer Cell 2005;7:575–89.[CrossRef][Medline]
38. Hanada N, Lo HW, Day CP, Pan Y, Nakajima Y, Hung MC. Co-regulation of B-Myb expression by E2F1 and EGF receptor. Mol Carcinog 2006;45:10–7.[CrossRef][Medline]
39. Lo HW, Xia W, Wei Y, Ali-Seyed M, Huang SF, Hung MC. Novel prognostic value of nuclear epidermal growth factor receptor in breast cancer. Cancer Res 2005;65:338–48.[Abstract/Free Full Text]
40. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–500.[Abstract/Free Full Text]
41. Pao W, Miller V, Zakowski M, 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 U S A 2004;101:13306–11.[Abstract/Free Full Text]
42. Giaccone G, Rodriguez JA. EGFR inhibitors: what have we learned from the treatment of lung cancer? Nat Clin Pract Oncol 2005;2:554–61.[CrossRef][Medline]
43. Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 2005;97:643–55.[Abstract/Free Full Text]
44. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005;2:e17.[CrossRef][Medline]
45. Stephens P, Hunter C, Bignell G, et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 2004;431:525–6.[Medline]
46. Fujimoto N, Wislez M, Zhang J, et al. High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor. Cancer Res 2005;65:11478–85.[Abstract/Free Full Text]
47. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–54.[CrossRef][Medline]
48. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.[Free Full Text]
49. Solit DB, Garraway LA, Pratilas CA, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 2006;439:358.[CrossRef][Medline]
50. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase-Akt pathway in human cancer. Nat Rev Cancer 2002;2:489–501.[CrossRef][Medline]
51. Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 2001;98:10314–9.[Abstract/Free Full Text]
52. Kobayashi S, Ji H, Yuza Y, et al. An alternative inhibitor overcomes resistance caused by a mutation of the epidermal growth factor receptor. Cancer Res 2005;65:7096–101.[Abstract/Free Full Text]
53. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73.[CrossRef][Medline]
54. Carter TA, Wodicka LM, Shah NP, et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A 2005;102:11011–6.[Abstract/Free Full Text]
55. Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 2005;23:2445–59.[Abstract/Free Full Text]
56. Baselga J, Albanell J, Ruiz A, et al. Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol 2005;23:5323–33.[Abstract/Free Full Text]
57. Rojo F, Tabernero J, Albanell J, et al. Pharmacodynamic studies of gefitinib (IRESSA) in tumour biopsy specimens from patients with advanced gastric carcinoma. J Clin Oncol. In press 2006.
58. Tsuchihashi Z, Khambata-Ford S, Hanna N, Janne PA. Responsiveness to cetuximab without mutations in EGFR. N Engl J Med 2005;353:208–9.[Free Full Text]
59. Bild AH, Yao G, Chang JT, et al. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 2006;439:353–7.[CrossRef][Medline]
60. Politi K, Zakowski MF, Fan PD, Schonfeld EA, Pao W, Varmus HE. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev 2006;20:1496–510.[Abstract/Free Full Text]
61. Felip E, Rojo F, Reck M, et al. Phase II pharmacodynamic trial of erlotinib in advanced non-small cell lung cancer (NSCLC) patients previously treated with platinum-based chemotherapy: FISH results. Am Soc Clin Oncol Annu Meet (Meet Abstr) 2006;24:7160.

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