EGFR tyrosine kinases inhibitors in cancer treatment: in vitro and in vivo evidence

Frontiers in Bioscience

Volumn 16, Issue 5, 2011, Pages 1962-1972

  Quatrale, Anna Elisa ^a   Porcelli, Letizia ^a   Silvestris, Nicola ^a   Colucci, Giuseppe ^a   Paradiso, Angelo ^a   Azzariti, Amalia ^a  

^a NATIONAL CANCER INSTITUTE GIOVANNI PAOLO II   (Italy)

Author keywords

Biological activity; Cancer treatment; EGFR tyrosine kinase inhibitors; Erlotinib; Gefitinib; Lapatinib; Mechanisms of action; Review

Indexed keywords

ANTINEOPLASTIC AGENT; EPIDERMAL GROWTH FACTOR RECEPTOR; ERLOTINIB; GEFITINIB; LAPATINIB; PROTEIN KINASE INHIBITOR; PROTEIN TYROSINE KINASE; QUINAZOLINE DERIVATIVE;

APOPTOSIS; CANCER INVASION; CELL DIVISION; DRUG ANTAGONISM; DRUG EFFECT; HUMAN; METASTASIS; NEOPLASM; NEOVASCULARIZATION (PATHOLOGY); PHYSIOLOGY; REVIEW; SIGNAL TRANSDUCTION;

ANTINEOPLASTIC AGENTS; APOPTOSIS; CELL DIVISION; HUMANS; NEOPLASM INVASIVENESS; NEOPLASM METASTASIS; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; PROTEIN KINASE INHIBITORS; PROTEIN-TYROSINE KINASES; QUINAZOLINES; RECEPTOR, EPIDERMAL GROWTH FACTOR; SIGNAL TRANSDUCTION;

EID: 79954988228     PISSN: 27686701     EISSN: 27686698     Source Type: Journal    
DOI: 10.2741/3833     Document Type: Article

References (65)

1. S. Sebastian, J. Settleman, S. J. Reshkin, A. Azzariti, A. Bellizzi and A. Paradiso: The complexity of targeting EGFR signalling in cancer: from expression to turnover, Biochim Biophys Acta 1766, 120-139 (2006) (Pubitemid 44175636)
2. N. Normanno, M. R. Maiello and A. De Luca: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFRTKIs): simple drugs with a complex mechanism of action? J Cell Physiol 194, 13-19 (2003) (Pubitemid 35424223)
3. R. N. Jorissen, F. Walker, N. Pouliot, T. P. Garrett, C. W. Ward and A. W. Burgess: Epidermal growth factor receptor: mechanisms of activation and signalling, Exp Cell Res 284, 31-53 (2003) (Pubitemid 36331965)
4. D. L. Cadena, C. L. Chan and G. N. Gill: The intracellular tyrosine kinase domain of the epidermal growth factor receptor undergoes a conformational change upon autophosphorylation, J Biol Chem 269, 260-265 (1994) (Pubitemid 24026653)
5. J. Stamos, M. X. Sliwkowski and C. Eigenbrot: Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor, J Biol Chem 277, 46265-46272 (2002) (Pubitemid 35417619)
6. E. R. Wood, A. T. Truesdale, O. B. McDonald, D. Yuan, A. Hassell, S. H. Dickerson, B. Ellis, C. Pennisi, E. Horne, K. Lackey, K. J. Alligood, D. W. Rusnak, T. M. Gilmer and L. Shewchuk: A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor offrate, and receptor activity in tumor cells, Cancer Res 64, 6652-6659 (2004) (Pubitemid 39297926)
7. L. N. Johnson, Protein kinase inhibitors: contributions from structure to clinical compounds, Q Rev Biophys 42, 1-40 (2009)
8. B. Zahorowska, P. J. Crowe and J. L. Yang: Combined therapies for cancer: a review of EGFR-targeted monotherapy and combination treatment with other drugs, J Cancer Res Clin Oncol 135, 1137-1148 (2009)
9. J. Von Pawel, Gefitinib (Iressa, ZD1839): a novel targeted approach for the treatment of solid tumors, Bull Cancer 91, E70-6 (2004)
10. A. Azzariti, L. Porcelli, G. Gatti, A. Nicolin and A. Paradiso: Synergic antiproliferative and antiangiogenic effects of EGFR and mTor inhibitors on pancreatic cancer cells, Biochem Pharmacol 75, 1035-1044 (2008)
11. G. Giannelli, C. Sgarra, L. Porcelli, A. Azzariti, S. Antonaci and A. Paradiso: EGFR and VEGFR as potential target for biological therapies in HCC cells, Cancer Lett 262, 257-264 (2008)
12. S. Sebastian, A. Azzariti, R. Accardi, D. Conti, B. Pilato, R. LaCalamita, L. Porcelli, G. M. Simone, S. Tommasi, M. Tommasino and A. Paradiso: Validation of gefitinib effectiveness in a broad panel of head and neck squamous carcinoma cells, Int J Mol Med 21, 809-817 (2008)
13. A. Azzariti, L. Porcelli, J. M. Xu, G. M. Simone and A. Paradiso: Prolonged exposure of colon cancer cells to the epidermal growth factor receptor inhibitor gefitinib (Iressa(TM)) and to the antiangiogenic agent ZD6474: Cytotoxic and biomolecular effects, World J Gastroenterol 12, 5140-5147 (2006) (Pubitemid 44355909)
14. A. Azzariti, J. M. Xu, L. Porcelli and A. Paradiso: The schedule-dependent enhanced cytotoxic activity of 7-ethyl-10-hydroxy- camptothecin (SN-38) in combination with Gefitinib (Iressa, ZD1839), Biochem Pharmacol 68, 135-144 (2004) (Pubitemid 38746549)
15. G. Giannelli, A. Azzariti, E. Fransvea, L. Porcelli, S. Antonaci and A. Paradiso: Laminin-5 offsets the efficacy of gefitinib ('Iressa') in hepatocellular carcinoma cells, Br J Cancer 91, 1964-1969 (2004) (Pubitemid 40065526)
16. J. M. Xu, A. Azzariti, M. Severino, B. Lu, G. Colucci and A. Paradiso: Characterization of sequence-dependent synergy between ZD1839 ("Iressa") and oxaliplatin, Biochem Pharmacol 66, 551-563 (2003) (Pubitemid 37281274)
17. K. Takeuchi and F. Ito: EGF receptor in relation to tumor development: molecular basis of responsiveness of cancer cells to EGFR-targeting tyrosine kinase inhibitors, FEBS J 277, 316-326 (2010)
18. M. L. Janmaat, F. A. Kruyt, J. A. Rodriguez and G. Giaccone: Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways, Clin Cancer Res 9, 2316-2326 (2003) (Pubitemid 36687658)
19. D. Busse, R. S. Doughty, T. T. Ramsey, W. E. Russell, J. O. Price, W. M. Flanagan, L. K. Shawver and C. L. Arteaga: Reversible G(1) arrest induced by inhibition of the epidermal growth factor receptor tyrosine kinase requires up-regulation of p27(KIP1) independent of MAPK activity, J Biol Chem 275, 6987-6995 (2000) (Pubitemid 30146243)
20. M. Ono and M. Kuwano: Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs, Clin Cancer Res 12, 7242-7251 (2006) (Pubitemid 46095395)
21. J. A. Engelman, P. A. Janne, C. Mermel, J. Pearlberg, T. Mukohara, C. Fleet, K. Cichowski, B. E. Johnson and L. C. Cantley: ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines, Proc Natl Acad Sci U S A 102, 3788-3793 (2005) (Pubitemid 40354690)
22. K. E. Matheny, C. E. Barbieri, J. C. Sniezek, C. L. Arteaga and J. A. Pietenpol: Inhibition of epidermal growth factor receptor signaling decreases p63 expression in head and neck squamous carcinoma cells, Laryngoscope 113, 936-939 (2003) (Pubitemid 36676585)
23. X. Zhou, M. Zheng, F. Chen, Y. Zhu, W. Yong, H. Lin, Y. Sun and X. Han: Gefitinib inhibits the proliferation of pancreatic cancer cells via cell cycle arrest, Anat Rec (Hoboken) 292, 1122-1127 (2009)
24. E. J. Lee, J. H. Whang, N. K. Jeon and J. Kim: The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses proliferation and invasion of human oral squamous carcinoma cells via p53 independent and MMP, uPAR dependent mechanism, Ann N Y Acad Sci 1095, 113-128 (2007) (Pubitemid 47092443)
25. C. J. Barnes, R. Bagheri-Yarmand, M. Mandal, Z. Yang, G. L. Clayman, W. K. Hong and R. Kumar: Suppression of epidermal growth factor receptor, mitogenactivated protein kinase, and Pak1 pathways and invasiveness of human cutaneous squamous cancer cells by the tyrosine kinase inhibitor ZD1839 (Iressa), Mol Cancer Ther 2, 345-351 (2003)
26. M. Koyama, Y. Matsuzaki, S. Yogosawa, T. Hitomi, M. Kawanaka and T. Sakai: ZD1839 induces p15INK4b and causes G1 arrest by inhibiting the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway, Mol Cancer Ther 6, 1579-1587 (2007) (Pubitemid 46954025)
27. M. Campiglio, A. Locatelli, C. Olgiati, N. Normanno, G. Somenzi, L. Vigano, M. Fumagalli, S. Menard and L. Gianni: Inhibition of proliferation and induction of apoptosis in breast cancer cells by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 ('Iressa') is independent of EGFR expression level, J Cell Physiol 198, 259-268 (2004) (Pubitemid 38133959)
28. L. A. Knight, F. Di Nicolantonio, P. Whitehouse, S. Mercer, S. Sharma, S. Glaysher, P. Johnson and I. A. Cree: The in vitro effect of gefitinib ('Iressa') alone and in combination with cytotoxic chemotherapy on human solid tumours, BMC Cancer 4, 83 (2004)
29. N. G. Anderson, T. Ahmad, K. Chan, R. Dobson and N. J. Bundred: ZD1839 (Iressa), a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, potently inhibits the growth of EGFR-positive cancer cell lines with or without erbB2 overexpression, Int J Cancer 94, 774-782 (2001) (Pubitemid 33032823)
30. J. Anido, P. Matar, J. Albanell, M. Guzman, F. Rojo, J. Arribas, S. Averbuch and J. Baselga: ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells, Clin Cancer Res 9, 1274-1283 (2003) (Pubitemid 36418377)
31. A. Azzariti, L. Porcelli, G. M. Simone, A. E. Quatrale, N. A. Colabufo, F. Berardi, R. Perrone, M. Zucchetti, M. D'Incalci, J. M. Xu and A. Paradiso: Tyrosine kinase inhibitors and multidrug resistance proteins: interactions and biological consequences, Cancer Chemother Pharmacol (2009)
32. F. Ciardiello, R. Caputo, R. Bianco, V. Damiano, G. Fontanini, S. Cuccato, S. De Placido, A. R. Bianco and G. Tortora: Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor, Clin Cancer Res 7, 1459-1465 (2001) (Pubitemid 32708703)
33. D. Kedrin, J. Wyckoff, P. J. Boimel, S. J. Coniglio, N. E. Hynes, C. L. Arteaga and J. E. Segall: ERBB1 and ERBB2 have distinct functions in tumor cell invasion and intravasation, Clin Cancer Res 15, 3733-3739 (2009)
34. Z. Yang, R. Bagheri-Yarmand, R. A. Wang, L. Adam, V. V. Papadimitrakopoulou, G. L. Clayman, A. El-Naggar, R. Lotan, C. J. Barnes, W. K. Hong and R. Kumar: The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses c-Src and Pak1 pathways and invasiveness of human cancer cells, Clin Cancer Res 10, 658-667 (2004) (Pubitemid 38174006)
35. F. M. Sirotnak, Studies with ZD1839 in preclinical models, Semin Oncol 30, 12-20 (2003) (Pubitemid 36307613)
36. Y. H. Ling, T. Li, Z. Yuan, M. Haigentz Jr, T. K. Weber and R. Perez-Soler: Erlotinib, an effective epidermal growth factor receptor tyrosine kinase inhibitor, induces p27KIP1 up-regulation and nuclear translocation in association with cell growth inhibition and G1/S phase arrest in human non-small-cell lung cancer cell lines, Mol Pharmacol 72, 248-258 (2007) (Pubitemid 47124105)
37. J. D. Moyer, E. G. Barbacci, K. K. Iwata, L. Arnold, B. Boman, A. Cunningham, C. DiOrio, J. Doty, M. J. Morin, M. P. Moyer, M. Neveu, V. A. Pollack, L. R. Pustilnik, M. M. Reynolds, D. Sloan, A. Theleman and P. Miller: Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase, Cancer Res 57, 4838-4848 (1997) (Pubitemid 27468992)
38. Y. Y. Lu, D. D. Jing, M. Xu, K. Wu and X. P. Wang: Anti-tumor activity of erlotinib in the BxPC-3 pancreatic cancer cell line, World J Gastroenterol 14, 5403-5411 (2008)
39. M. Hidalgo, Erlotinib: preclinical investigations, Oncology (Williston Park) 17, 11-16 (2003)
40. J. Chen, M. Smith, K. Kolinsky, V. Adames, N. Mehta, L. Fritzky, M. Rashed, E. Wheeldon, M. Linn and B. Higgins: Antitumor activity of HER1/EGFR tyrosine kinase inhibitor erlotinib, alone and in combination with CPT-11 (irinotecan) in human colorectal cancer xenograft models, Cancer Chemother Pharmacol 59, 651-659 (2007) (Pubitemid 46295130)
41. S. S. Ng, M. S. Tsao, T. Nicklee and D. W. Hedley: Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva, on downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma, Mol Cancer Ther 1, 777-783 (2002)
42. R. W. Akita and M. X. Sliwkowski: Preclinical studies with Erlotinib (Tarceva), Semin Oncol 30, 15-24 (2003) (Pubitemid 36828624)
43. D. R. Emlet, K. A. Brown, D. L. Kociban, A. A. Pollice, C. A. Smith, B. B. Ong and S. E. Shackney: 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, Mol Cancer Ther 6, 2664-2674 (2007) (Pubitemid 350058147)
44. G. Schaefer, L. Shao, K. Totpal and R. W. Akita: Erlotinib directly inhibits HER2 kinase activation and downstream signaling events in intact cells lacking epidermal growth factor receptor expression, Cancer Res 67, 1228-1238 (2007)
45. Y. Jin, K. K. Iwata, A. Belldegrun, R. Figlin, A. Pantuck, Z. F. Zhang, R. Lieberman and J. Rao: Effect of an epidermal growth factor receptor tyrosine kinase inhibitor on actin remodeling in an in vitro bladder cancer carcinogenesis model, Mol Cancer Ther 5, 1754-1763 (2006) (Pubitemid 44323243)
46. R. Diaz, P. A. Nguewa, R. Parrondo, C. Perez-Stable, I. Manrique, M. Redrado, R. Catena, M. Collantes, I. Penuelas, J. A. Diaz-Gonzalez and A. Calvo: Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model, BMC Cancer 10, 188 (2010)
47. D. W. Rusnak, K. J. Alligood, R. J. Mullin, G. M. Spehar, C. Arenas-Elliott, A. M. Martin, Y. Degenhardt, S. K. Rudolph, T. F. Haws Jr, B. L. Hudson-Curtis and T. M. Gilmer: Assessment of epidermal growth factor receptor (EGFR, ErbB1) and HER2 (ErbB2) protein expression levels and response to lapatinib (Tykerb, GW572016) in an expanded panel of human normal and tumour cell lines, Cell Prolif 40, 580-594 (2007) (Pubitemid 47063294)
48. V. W. Lui, C. P. Lau, K. Ho, M. H. Ng, S. H. Cheng, S. W. Tsao, C. M. Tsang, K. I. Lei, A. T. Chan and T. S. Mok: Anti-invasion, anti-proliferation and anoikis-sensitization activities of lapatinib in nasopharyngeal carcinoma cells, Invest New Drugs (2010)
49. D. Zhang, A. Pal, W. G. Bornmann, F. Yamasaki, F. J. Esteva, G. N. Hortobagyi, C. Bartholomeusz and N. T. Ueno: Activity of lapatinib is independent of EGFR expression level in HER2-overexpressing breast cancer cells, Mol Cancer Ther 7, 1846-1850 (2008)
50. G. E. Konecny, M. D. Pegram, N. Venkatesan, R. Finn, G. Yang, M. Rahmeh, M. Untch, D. W. Rusnak, G. Spehar, R. J. Mullin, B. R. Keith, T. M. Gilmer, M. Berger, K. C. Podratz and D. J. Slamon: Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells, Cancer Res 66, 1630-1639 (2006) (Pubitemid 43259947)
51. D. W. Rusnak, K. Lackey, K. Affleck, E. R. Wood, K. J. Alligood, N. Rhodes, B. R. Keith, D. M. Murray, W. B. Knight, R. J. Mullin and T. M. Gilmer: The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo, Mol Cancer Ther 1, 85-94 (2001)
52. W. Xia, R. J. Mullin, B. R. Keith, L. H. Liu, H. Ma, D. W. Rusnak, G. Owens, K. J. Alligood and N. L. Spector: Antitumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways, Oncogene 21, 6255-6263 (2002)
53. Y. Zhou, S. Li, Y. P. Hu, J. Wang, J. Hauser, A. N. Conway, M. A. Vinci, L. Humphrey, E. Zborowska, J. K. Willson and M. G. Brattain: Blockade of EGFR and ErbB2 by the novel dual EGFR and ErbB2 tyrosine kinase inhibitor GW572016 sensitizes human colon carcinoma GEO cells to apoptosis, Cancer Res 66, 404-411 (2006) (Pubitemid 43166048)
54. A. D'Alessio, A. De Luca, M. R. Maiello, L. Lamura, A. M. Rachiglio, M. Napolitano, M. Gallo and N. Normanno: Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells, Breast Cancer Res Treat (2009)
55. Z. A. Wainberg, A. Anghel, A. J. Desai, R. Ayala, T. Luo, B. Safran, M. S. Fejzo, J. R. Hecht, D. J. Slamon and R. S. Finn: Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo, Clin Cancer Res 16, 1509-1519 (2010)
56. N. Kondo, M. Tsukuda, Y. Ishiguro, M. Kimura, K. Fujita, A. Sakakibara, H. Takahashi, G. Toth and H. Matsuda: Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma, Oncol Rep 23, 957-963 (2010)
57. G. E. Konecny, N. Venkatesan, G. Yang, J. Dering, C. Ginther, R. Finn, M. Rahmeh, M. S. Fejzo, D. Toft, S. W. Jiang, D. J. Slamon and K. C. Podratz: Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells, Br J Cancer 98, 1076-1084 (2008) (Pubitemid 351399811)
58. P. S. Hegde, D. Rusnak, M. Bertiaux, K. Alligood, J. Strum, R. Gagnon and T. M. Gilmer: Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles, Mol Cancer Ther 6, 1629-1640 (2007) (Pubitemid 46954030)
59. M. Scaltriti, C. Verma, M. Guzman, J. Jimenez, J. L. Parra, K. Pedersen, D. J. Smith, S. Landolfi, S. Ramon y Cajal, J. Arribas and J. Baselga: Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumabdependent cell cytotoxicity, Oncogene 28, 803-814 (2009)
60. G. J. Riely, Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer, J Thorac Oncol 3, S146-9 (2008) (Pubitemid 351786747)
61. N. Minkovsky and A. Berezov: BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors, Curr Opin Investig Drugs 9, 1336-1346 (2008)
62. C. P. Belani, The role of irreversible EGFR inhibitors in the treatment of non-small cell lung cancer: overcoming resistance to reversible EGFR inhibitors, Cancer Invest 28, 413-423 (2010)
63. L. V. Sequist, B. Besse, T. J. Lynch, V. A. Miller, K. K. Wong, B. Gitlitz, K. Eaton, C. Zacharchuk, A. Freyman, C. Powell, R. Ananthakrishnan, S. Quinn and J. C. Soria: Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer, J Clin Oncol 28, 3076-3083 (2010)
64. A. J. Gonzales, K. E. Hook, I. W. Althaus, P. A. Ellis, E. Trachet, A. M. Delaney, P. J. Harvey, T. A. Ellis, D. M. Amato, J. M. Nelson, D. W. Fry, T. Zhu, C. M. Loi, S. A. Fakhoury, K. M. Schlosser, K. E. Sexton, R. T. Winters, J. E. Reed, A. J. Bridges, D. J. Lettiere, D. A. Baker, J. Yang, H. T. Lee, H. Tecle and P. W. Vincent: Antitumor activity and pharmacokinetic properties of PF-00299804, a secondgeneration irreversible pan-erbB receptor tyrosine kinase inhibitor, Mol Cancer Ther 7, 1880-1889 (2008)
65. G. N. Naumov, M. B. Nilsson, T. Cascone, A. Briggs, O. Straume, L. A. Akslen, E. Lifshits, L. A. Byers, L. Xu, H. K. Wu, P. Janne, S. Kobayashi, B. Halmos, D. Tenen, X. M. Tang, J. Engelman, B. Yeap, J. Folkman, B. E. Johnson and J. V. Heymach: Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance, Clin Cancer Res 15, 3484-3494 (2009)