Skip to main content Accessibility help
  • Print publication year: 2013
  • Online publication date: February 2015

8 - Tyrosine kinome profiling: oncogenic mutations and therapeutic targeting in cancer

from Part 1.2 - Analytical techniques: analysis of RNA
    • By Paramita Ghosh, Departments of Biochemistry and Molecular Medicine, and Urology, University of California David School of Medicine, Sacramento, and VA Northern Health Care System, Mather, CA, USA, Yun Qiu, Department of Pharmacology and Experimentalherapeutics, University of Maryland School of Medicine, Baltimore, MD, USA, Ling-Yu Wang, Department of Stem Cell Biology and Regenerative Medicine, Kimmel Cancer Center,homas Jeferson University, Philadelphia, PA, USA, Hsing-Jien Kung, Departments of Biochemistry and Molecular Medicine, and Urology, University of California David School of Medicine, Sacramento, CA, USA
  • Edited by Edward P. Gelmann, Columbia University, New York, Charles L. Sawyers, Memorial Sloan-Kettering Cancer Center, New York, Frank J. Rauscher, III
  • Publisher: Cambridge University Press
  • DOI:
  • pp 58-75



Protein phosphorylation was first discovered by Fischer and Krebs in the mid-1950s (1), and it has been generally accepted that reversible protein phosphorylation regulates virtually every physiological event in mammalian cells. There are approximately 518 protein kinases in human cells. Among them, 89 are tyrosine kinases (2). Phosphorylation by protein tyrosine kinases is crucial to the control of development and growth of multi-cellular organisms. Deregulation or mutation of tyrosine kinases in human cancers has been repeatedly reported in the literature (3). About a quarter of tyrosine kinases were originally discovered as oncogenes, and represent the largest family of oncogenes. Tyrosine kinases are classified as receptor and non-receptor tyrosine kinases. Both classes of tyrosine kinases catalyze the addition of a phosphoryl group on a tyrosine residue but at different locations within the cell – whereas receptor tyrosine kinases (RTKs) are transmembrane proteins, non-receptor tyrosine kinases (NRTKs) are intra-cellular. At present, there are 57 known RTKs in mammalian cells classified into about 20 families, whereas 32 are NRTK, classified into approximately 10 families (Table 8.1).

Fischer, EH, Krebs, EG. Conversion of phosphorylase b to phosphorylase a in muscle extracts. Journal of Biological Chemistry 1955;216:121–32.
Manning, G, Whyte, DB, Martinez, R, Hunter, T, Sudarsanam, S. The protein kinase complement of the human genome. Science 2002;298:1912–34.
Blume-Jensen, P, Hunter, T. Oncogenic kinase signalling. Nature 2001;411:355–65.
Robinson, DR, Wu, YM, Lin, SF. The protein tyrosine kinase family of the human genome. Oncogene 2000;19:5548–57.
Koegl, M, Zlatkine, P, Ley, SC, Courtneidge, SA, Magee, AI. Palmitoylation of multiple Src-family kinases at a homologous N-terminal motif. Biochemical Journal 1994;303(Pt ):749–53.
Resh, MD. Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins. Biochimica et Biophysica Acta 1999;1451:1–16.
Boggon, TJ, Eck, MJ. Structure and regulation of Src family kinases. Oncogene 2004;23:7918–27.
Hauck, CR, Klingbeil, CK, Schlaepfer, DD. Focal adhesion kinase functions as a receptor-proximal signaling component required for directed cell migration. Immunologic Research 2000;21:293–303.
Qiu, Y, Kung, HJ. Signaling network of the Btk family kinases. Oncogene 2000;19:5651–61.
Olayioye, MA, Neve, RM, Lane, HA, Hynes, NE. The ERBB signaling network: receptor heterodimerization in development and cancer. EMBO Journal 2000;19:3159–67.
Talbert-Slagle, K, DiMaio, D. The bovine papillomavirus E5 protein and the PDGF beta receptor: it takes two to tango. Virology 2009;384:345–51.
Bhola, NE, Grandis, JR. Crosstalk between G-protein-coupled receptors and epidermal growth factor receptor in cancer. Frontiers in Bioscience 2008;13:1857–65.
Murakami, M, Elfenbein, A, Simons, M. Non-canonical fibroblast growth factor signalling in angiogenesis. Cardiovascular Research 2008;78:223–31.
Wang, SC, Hung, MC. Nuclear translocation of the epidermal growth factor receptor family membrane tyrosine kinase receptors. Clinical Cancer Research 2009;15:6484–9.
Tschoep, K, Kohlmann, A, Schlemmer, M, Haferlach, T, Issels, RD. Gene expression profiling in sarcomas. Critical Reviews in Oncology/Hematology 2007;63:111–24.
Ordonez, JL, Martins, AS, Osuna, D, Madoz-Gurpide, J, de Alava, E. Targeting sarcomas: therapeutic targets and their rational. Seminars in Diagnostic Pathology 2008;25:304–16.
Antonescu, CR. Targeted therapy of cancer: new roles for pathologists in identifying GISTs and other sarcomas. Modern Pathology 2008;21 Suppl 2:S31–6.
von Mehren, M. The role of adjuvant and neoadjuvant therapy in gastrointestinal stromal tumors. Current Opinion in Oncology 2008;20:428–32.
Collett, MS, Erikson, RL. Protein kinase activity associated with the avian sarcoma virus src gene product. Proceedings of the National Academy of Sciences USA 1978;75:2021–4.
Hunter, T, Sefton, BM. Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proceedings of the National Academy of Sciences USA 1980;77:1311–15.
Ushiro, H, Cohen, S.Identification of phosphotyrosine as a product of epidermal growth factor-activated protein kinase in A-431 cell membranes. Journal of Biological Chemistry 1980;255:8363–5.
Kasuga, M, Karlsson, FA, Kahn, CR. Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. Science 1982;215:185–7.
Wilks, AF. Two putative protein-tyrosine kinases identified by application of the polymerase chain reaction. Proceedings of the National Academy of Sciences USA 1989;86:1603–7.
Hutton, LA, deVellis, J, Perez-Polo, JR.Expression of p75NGFR TrkA, and TrkB mRNA in rat C6 glioma and type I astrocyte cultures. Journal of Neuroscience Research 1992;32:375–83.
Paria, BC, Das, SK, Andrews, GK, Dey, SK. Expression of the epidermal growth factor receptor gene is regulated in mouse blastocysts during delayed implantation. Proceedings of the National Academy of Sciences USA 1993;90:55–9.
Robinson, D, He, F, Pretlow, T, Kung, HJ. A tyrosine kinase profile of prostate carcinoma. Proceedings of the National Academy of Sciences USA 1996;93:5958–62.
Layfield, LJ, Bernard, PS, Goldstein, NS.Color multiplex polymerase chain reaction for quantitative analysis of epidermal growth factor receptor genes in colorectal adenocarcinoma. Journal of Surgical Oncology 2003;83:227–31.
Persson, K, Hamby, K, Ugozzoli, LA. Four-color multiplex reverse transcription polymerase chain reaction–overcoming its limitations. Annals of Biochemistry 2005;344:33–42.
Iyer, VR, Eisen, MB, Ross, DT, et al. The transcriptional program in the response of human fibroblasts to serum. Science 1999;283:83–7.
Italiano, A, Attias, R, Aurias, A, et al. Molecular cytogenetic characterization of a metastatic lung sarcomatoid carcinoma: 9p23 neocentromere and 9p23-p24 amplification including JAK2 and JMJD2C. Cancer Genetics and Cytogenetics 2006;167:122–30.
Martinez-Ramirez, A, Urioste, M, Melchor, L, et al. Analysis of myelodysplastic syndromes with complex karyotypes by high-resolution comparative genomic hybridization and subtelomeric CGH array. Genes, Chromosomes and Cancer 2005;42:287–98.
Pollack, JR, Perou, CM, Alizadeh, AA, et al. Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nature Genetics 1999;23:41–6.
Somiari, SB, Shriver, CD, He, J, et al. Global search for chromosomal abnormalities in infiltrating ductal carcinoma of the breast using array-comparative genomic hybridization. Cancer Genetics and Cytogenetics 2004;155:108–18.
Sorlie, T, Tibshirani, R, Parker, J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proceedings of the National Academy of Sciences USA 2003;100:8418–23.
van de Vijver, MJ, He, YD, van ‘t Veer, LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. New England Journal of Medicine 2002;347:1999–2009.
Kononen, J, Bubendorf, L, Kallioniemi, A, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nature Medicine 1998;4:844–7.
Ibarrola, N, Kalume, DE, Gronborg, M, Iwahori, A, Pandey, A. A proteomic approach for quantitation of phosphorylation using stable isotope labeling in cell culture. Annals of Chemistry 2003;75:6043–9.
Nollau, P, Mayer, BJ. Profiling the global tyrosine phosphorylation state by Src homology 2 domain binding. Proceedings of the National Academy of Sciences USA 2001;98:13531–6.
Dierck, K, Machida, K, Voigt, A, et al. Quantitative multiplexed profiling of cellular signaling networks using phosphotyrosine-specific DNA-tagged SH2 domains. Nature Methods 2006;3:737–44.
Nielsen, UB, Cardone, MH, Sinskey, AJ, MacBeath, G, Sorger, PK. Profiling receptor tyrosine kinase activation by using Ab microarrays. Proceedings of the National Academy of Sciences USA 2003;100:9330–5.
Salomon, AR, Ficarro, SB, Brill, LM, et al. Profiling of tyrosine phosphorylation pathways in human cells using mass spectrometry. Proceedings of the National Academy of Sciences USA 2003;100:443–8.
Machida, K, Mayer, BJ, Nollau, P. Profiling the global tyrosine phosphorylation state. Molecular and Cell Proteomics 2003;2:215–33.
Olsen, JV, Blagoev, B, Gnad, F, et al. Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2006;127:635–48.
Rikova, K, Guo, A, Zeng, Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007;131:1190–203.
Irish, JM, Hovland, R, Krutzik, PO, et al. Single cell profiling of potentiated phospho-protein networks in cancer cells. Cell 2004;118:217–28.
Zhu, H, Klemic, JF, Chang, S, et al. Analysis of yeast protein kinases using protein chips. Nature Genetics 2000;26:283–9.
Tyner, JW, Walters, DK, Willis, SG, et al. RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia. Blood 2008;111:2238–45.
Davies, H, Bignell, GR, Cox, C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–54.
Rajagopalan, H, Bardelli, A, Lengauer, C, et al. Tumorigenesis:RAF/RAS oncogenes and mismatch-repair status. Nature 2002;418:934.
Bardelli, A, Parsons, DW, Silliman, N, et al. Mutational analysis of the tyrosine kinome in colorectal cancers. Science 2003;300:949.
Lynch, TJ, Bell, DW, Sordella, R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New England Journal of Medicine 2004;350:2129–39.
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.
Davies, H, Hunter, C, Smith, R, et al. Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Research 2005;65:7591–5.
Shigematsu, H, Takahashi, T, Nomura, M, et al. Somatic mutations of the her2 kinase domain in lung adenocarcinomas. Cancer Research 2005;65:1642–6.
Stephens, P, Edkins, S, Davies, H, et al. A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer. Nature Genetics 2005;37:590–2.
Balakrishnan, A, Bleeker, FE, Lamba, S, et al. Novel somatic and germline mutations in cancer candidate genes in glioblastoma, melanoma, and pancreatic carcinoma. Cancer Research 2007;67:3545–50.
Greenman, C, Stephens, P, Smith, R, et al. Patterns of somatic mutation in human cancer genomes. Nature 2007;446:153–8.
Hunter, C, Smith, R, Cahill, DP, et al. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Research 2006;66:3987–91.
Stephens, P, Hunter, C, Bignell, G, et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 2004;431:525–6.
Huang, SF, Liu, HP, Li, LH, et al. High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clinical Cancer Research 2004;10:8195–203.
Taron, M, Ichinose, Y, Rosell, R, et al. Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clinical Cancer Research 2005;11:5878–85.
Dai, B, Kim, O, Xie, Y, et al. Tyrosine kinase Etk/BMX is up-regulated in human prostate cancer and its overexpression induces prostate intraepithelial neoplasia in mouse. Cancer Research 2006;66:8058–64.
Walters, DK, Mercher, T, Gu, TL, et al. Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell 2006;10:65–75.
Lengyel, E, Sawada, K, Salgia, R. Tyrosine kinase mutations in human cancer. Current Molecular Medicine 2007;7:77–84.
Shu, HK, Pelley, RJ, Kung, HJ. Tissue-specific transformation by epidermal growth factor receptor: a single point mutation within the ATP-binding pocket of the erbB product increases its intrinsic kinase activity and activates its sarcomagenic potential. Proceedings of the National Academy of Sciences USA 1990;87:9103–7.
Irmer, D, Funk, JO, Blaukat, A. EGFR kinase domain mutations – functional impact and relevance for lung cancer therapy. Oncogene 2007;26:5693–701.
Rosell, R, Taron, M, Reguart, N, Isla, D, Moran, T. Epidermal growth factor receptor activation: how exon 19 and 21 mutations changed our understanding of the pathway. Clinical Cancer Research 2006;12:7222–31.
Chen, YR, Fu, YN, Lin, CH, et al. Distinctive activation patterns in constitutively active and gefitinib-sensitive EGFR mutants. Oncogene 2006;25:1205–15.
Heinrich, MC, Corless, CL, Duensing, A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003;299:708–10.
Small, D. FLT3 mutations: biology and treatment. Hematology 2006:178–84.
Frohling, S, Scholl, C, Levine, RL, et al. Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles. Cancer Cell 2007;12:501–13.
Iwashita, T, Murakami, H, Kurokawa, K, et al. A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations. Biochemical and Biophysical Research Communications 2000;268:804–8.
Lee, JW, Soung, YH, Kim, SY, et al. ERBB2 kinase domain mutation in the lung squamous cell carcinoma. Cancer Letters 2006;237:89–94.
Lee, JW, Soung, YH, Kim, SY, et al. ERBB2 kinase domain mutation in a gastric cancer metastasis. APMIS 2005;113:683–7.
Sasaki, H, Shimizu, S, Endo, K, et al. EGFR and erbB2 mutation status in Japanese lung cancer patients. International Journal of Cancer 2006;118:180–4.
Soung, YH, Lee, JW, Kim, SY, et al. Somatic mutations of the ERBB4 kinase domain in human cancers. International Journal of Cancer 2006;118:1426–9.
Huusko, P, Ponciano-Jackson, D, Wolf, M, et al. Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer. Nature Genetics 2004;36:979–83.
Ma, PC, Kijima, T, Maulik, G, et al. c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Research 2003;63:6272–81.
Kuan, CT, Wikstrand, CJ, Bigner, DD. EGF mutant receptor vIII as a molecular target in cancer therapy. Endocrine-related cancer 2001;8:83–96.
Fung, YK, Lewis, WG, Crittenden, LB, Kung, HJ. Activation of the cellular oncogene c-erbB by LTR insertion: molecular basis for induction of erythroblastosis by avian leukosis virus. Cell 1983;33:357–68.
Nilsen, TW, Maroney, PA, Goodwin, RG, et al. c-erbB activation in ALV-induced erythroblastosis: novel RNA processing and promoter insertion result in expression of an amino-truncated EGF receptor. Cell 1985;41:719–26.
Maihle, NJ, Raines, MA, Flickinger, TW, Kung, HJ. Proviral insertional activation of c-erbB: differential processing of the protein products arising from two alternate transcripts. Molecular and Cellular Biology 1988;8:4868–76.
Chu, CT, Everiss, KD, Wikstrand, CJ, et al. Receptor dimerization is not a factor in the signalling activity of a transforming variant epidermal growth factor receptor (EGFRvIII). Biochemical Journal 1997;324 (Pt ):855–61.
Luwor, RB, Zhu, HJ, Walker, F, et al. The tumor-specific de2–7 epidermal growth factor receptor (EGFR) promotes cells survival and heterodimerizes with the wild-type EGFR. Oncogene 2004;23:6095–104.
Ma, PC, Jagadeeswaran, R, Jagadeesh, S, et al. Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Research 2005;65:1479–88.
Boldrini, L, Ursino, S, Gisfredi, S, et al. Expression and mutational status of c-kit in small-cell lung cancer: prognostic relevance. Clinical Cancer Research 2004;10:4101–8.
Sattler, M, Salgia, R. Targeting c-Kit mutations: basic science to novel therapies. Leukemia Research 2004;28 Suppl 1:S11–20.
Brenner, TL, Adams, VR. First MAb approved for treatment of metastatic breast cancer. Journal of the American Pharmaceutical Association (Washington) 1999;39:236–8.
Baselga, J.The EGFR as a target for anticancer therapy–focus on cetuximab. European Journal of Cancer 2001;37 Suppl 4:S16–22.
Dediu, M, Median, D, Alexandru, A, Vremes, G, Gal, C.Tyrosine kinase inhibitors in non-small cell lung and pancreatic cancer: the emerging role of erlotinib. Journal of BUON 2007;12 Suppl 1:S137–49.
Juergens, R, Brahmer, J. Targeting the epidermal growth factor receptor in non-small-cell lung cancer: who, which, when, and how? Current Oncology Reports 2007;9:255–64.
Cebe-Suarez, S, Zehnder-Fjallman, A, Ballmer-Hofer, K. The role of VEGF receptors in angiogenesis; complex partnerships. Cellular and Molecular Life Science 2006;63:601–15.
Fox, WD, Higgins, B, Maiese, KM, et al. Antibody to vascular endothelial growth factor slows growth of an androgen-independent xenograft model of prostate cancer. Clinical Cancer Research 2002;8:3226–31.
Gravalos, C, Cassinello, J, Fernandez-Ranada, I, Holgado, E. Role of tyrosine kinase inhibitors in the treatment of advanced colorectal cancer. Clinical Colorectal Cancer 2007;6:691–9.
Los, M, Roodhart, JM, Voest, EE. Target practice: lessons from Phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. The Oncologist 2007;12:443–50.
Chang, YM, Kung, HJ, Evans, CP. Nonreceptor tyrosine kinases in prostate cancer. Neoplasia 2007;9:90–100.
Schindler, T, Bornmann, W, Pellicena, P, et al. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000;289:1938–42.
Sawyers, CL, Hochhaus, A, Feldman, E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis:results of a Phase II study. Blood 2002;99:3530–9.
Nam, S, Kim, D, Cheng, JQ, et al. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Research 2005;65:9185–9.
Schittenhelm, MM, Shiraga, S, Schroeder, A, et al. Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Research 2006;66:473–81.
Shah, NP, Lee, FY, Luo, R, et al. Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis. Blood 2006;108:286–91.
Steinberg, M. Dasatinib:a tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia. Clinical Therapeutics 2007;29:2289–308.
Hennequin, LF, Allen, J, Breed, J, et al. N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. Journal of Medicinal Chemistry 2006;49:6465–88.
Fizazi, K. The role of Src in prostate cancer. Annals of Oncology 2007;18:1765–73.
Golas, JM, Arndt, K, Etienne, C, et al. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Research 2003;63:375–81.
Golas, JM, Lucas, J, Etienne, C, et al. SKI-606, a Src/Abl inhibitor with in vivo activity in colon tumor xenograft models. Cancer Research 2005;65:5358–64.
Frame, D.New strategies in controlling drug resistance. Journal of Managed Care Pharmacy 2007;13:13–17.
Apperley, JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncology 2007;8:1018–29.
Gorre, ME, Mohammed, M, Ellwood, K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001;293:876–80.
Gambacorti-Passerini, C, Zucchetti, M, Russo, D, et al. Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clinical Cancer Research 2003;9:625–32.
Carraway, KL, Price-Schiavi, SA, Komatsu, M, et al. Muc4/sialomucin complex in the mammary gland and breast cancer. Journal of Mammary Gland Biology and Neoplasia 2001;6:323–37.
Melo, JV, Chuah, C. Resistance to imatinib mesylate in chronic myeloid leukaemia. Cancer Letters 2007;249:121–32.
Debiec-Rychter, M, Cools, J, Dumez, H, et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology 2005;128:270–9.
Kobayashi, S, Boggon, TJ, Dayaram, T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. New England Journal of Medicine 2005;352:786–92.
Michalczyk, A, Kluter, S, Rode, HB, et al. Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR. Bioorganic and Medicinal Chemistry 2008;16:3482–8.
Yun, CH, Boggon, TJ, Li, Y, et al. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 2007;11:217–27.
Bean, J, Riely, GJ, Balak, M, et al. Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clinical Cancer Research 2008;14:7519–25.
Lee, JW, Soung, YH, Seo, SH, et al. Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas. Clinical Cancer Research 2006;12:57–61.
Gottesman, MM, Fojo, T, Bates, SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nature Reviews Cancer 2002;2:48–58.
Thomas, J, Wang, L, Clark, RE, Pirmohamed, M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood 2004;104:3739–45.
Burger, H, van Tol, H, Brok, M, et al. Chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the ABCG2 (BCRP) and ABCB1 (MDR1) drug transport pumps. Cancer Biology and Therapy 2005;4:747–52.
Crossman, LC, Druker, BJ, Deininger, MW, et al. hOCT 1 and resistance to imatinib. Blood 2005;106:1133–4;author reply 4.
Ritter, CA, Perez-Torres, M, Rinehart, C, et al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ERBB ligands and remain dependent on the ERBB receptor network. Clinical Cancer Research 2007;13:4909–19.
Camirand, A, Lu, Y, Pollak, M. Co-targeting HER2/ERBB2 and insulin-like growth factor-1 receptors causes synergistic inhibition of growth in HER2-overexpressing breast cancer cells. Medical Science Monitor 2002;8:BR521–6.
Donato, NJ, Wu, JY, Stapley, J, et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 2003;101:690–8.
Burchert, A, Cai, D, Hofbauer, LC, et al. Interferon consensus sequence binding protein (ICSBP;IRF-8) antagonizes BCR/ABL and down-regulates bcl-2. Blood 2004;103:3480–9.
Wendel, HG, de Stanchina, E, Cepero, E, et al. Loss of p53 impedes the antileukemic response to BCR-ABL inhibition. Proceedings of the National Academy of Sciences USA 2006;103:7444–9.
Burchert, A, Wang, Y, Cai, D, et al. Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia 2005;19:1774–82.
Nagata, Y, Lan, KH, Zhou, X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004;6:117–27.
Le, XF, Claret, FX, Lammayot, A, et al. The role of cyclin-dependent kinase inhibitor p27Kip1 in anti-HER2 antibody-induced G1 cell cycle arrest and tumor growth inhibition. Journal of Biological Chemistry 2003;278:23 441–50.
Engelman, JA, Zejnullahu, K, Mitsudomi, T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316:1039–43.
Turke, AB, Zejnullahu, K, Wu, YL, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell;2010;17:77–88.
Engelman, JA, Janne, PA. Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clinical Cancer Research 2008;14:2895–9.
Bean, J, Brennan, C, Shih, JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proceedings of the National Academy of Sciences USA 2007;104:20 932–7.
Emlet, DR, Brown, KA, Kociban, DL, et al. Response to trastuzumab, erlotinib, and bevacizumab, alone and in combination, is correlated with the level of human epidermal growth factor receptor-2 expression in human breast cancer cell lines. Molecular Cancer Therapeutics 2007;6:2664–74.
Thariat, J, Milas, L, Ang, KK.Integrating radiotherapy with epidermal growth factor receptor antagonists and other molecular therapeutics for the treatment of head and neck cancer. International Journal of Radiation Oncology, Biology, Physics 2007;69:974–84.
Carter, TA, Wodicka, LM, Shah, NP, et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proceedings of the National Academy of Sciences USA 2005;102:11 011–6.
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.
Montemurro, F, Valabrega, G, Aglietta, M. Lapatinib:a dual inhibitor of EGFR and HER2 tyrosine kinase activity. Expert Opinion in Biological Therapy 2007;7:257–68.
Mellinghoff, IK, Tran, C, Sawyers, CL. Growth inhibitory effects of the dual ERBB1/ERBB2 tyrosine kinase inhibitor PKI-166 on human prostate cancer xenografts. Cancer Research 2002;62:5254–9.
Dewji, MR.Early Phase I data on an irreversible pan-erb inhibitor:CI-1033. What did we learn?Journal of Chemotherapy (Florence, Italy) 2004;16 Suppl 4:44–8.
Agus, DB, Akita, RW, Fox, WD, et al. Targeting ligand-activated ERBB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2002;2:127–37.
Baselga, J. A new anti-ERBB2 strategy in the treatment of cancer: prevention of ligand-dependent ERBB2 receptor heterodimerization. Cancer Cell 2002;2:93–5.
Ratain, MJ, Eisen, T, Stadler, WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology 2006;24:2505–12.
Mendel, DB, Laird, AD, Xin, X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clinical Cancer Research 2003;9:327–37.
Wiedmann, MW, Caca, K. Molecularly targeted therapy for gastrointestinal cancer. Current Cancer Drug Targets 2005;5:171–93.
Moasser, MM, Srethapakdi, M, Sachar, KS, Kraker, AJ, Rosen, N. Inhibition of Src kinases by a selective tyrosine kinase inhibitor causes mitotic arrest. Cancer Research 1999;59:6145–52.
Wisniewski, D, Lambek, CL, Liu, C, et al. Characterization of potent inhibitors of the Bcr-Abl and the c-kit receptor tyrosine kinases. Cancer Research 2002;62:4244–55.