Gatekeeper mutations mediate resistance to BRAF-targeted therapies

Science Translational Medicine

Volumn 2, Issue 35, 2010, Pages

  Whittaker, Steven ^a   Kirk, Ruth ^a   Hayward, Robert ^a   Zambon, Alfonso ^a   Viros, Amaya ^a   Cantarino, Neus ^a   Affolter, Annette ^a   Nourry, Arnaud ^a   Niculescu Duvaz, Dan ^a   Springer, Caroline ^a   Marais, Richard ^a  

^a INSTITUTE OF CANCER RESEARCH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2 [4 (2 DIMETHYLAMINOETHOXY)PHENYL] 4 (1 HYDROXYIMINO 5 INDANYL) 5 (4 PYRIDINYL) 1H IMIDAZOLE; ANTINEOPLASTIC AGENT; B RAF KINASE; B RAF KINASE INHIBITOR; CHIR 265; PLX 4720; SORAFENIB; UNCLASSIFIED DRUG; PROTEIN KINASE INHIBITOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL CULTURE; CANCER INHIBITION; CANCER RESISTANCE; CELL PROLIFERATION; CONTROLLED STUDY; DRUG EFFECT; DRUG MECHANISM; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SCREENING; DRUG SELECTIVITY; DRUG SENSITIVITY; DRUG STRUCTURE; DRUG TARGETING; EMBRYO; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; MOUSE; MUTATIONAL ANALYSIS; NONHUMAN; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; ANIMAL; BIOCATALYSIS; CELL LINE; CHEMICAL STRUCTURE; DRUG ANTAGONISM; DRUG RESISTANCE; ENZYMOLOGY; GENETICS; MUTATION; NEOPLASM;

ANIMALS; ANTINEOPLASTIC AGENTS; BIOCATALYSIS; CELL LINE; DRUG RESISTANCE, NEOPLASM; HUMANS; MICE; MODELS, MOLECULAR; MUTATION; NEOPLASMS; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS B-RAF;

EID: 77955602211     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.3000758     Document Type: Article

References (46)

1. A. Levitzki, Signal-transduction therapy. A novel approach to disease management. Eur. J. Biochem. 226, 1-13 (1994).
2. J. Zhang, P. L. Yang, N. S. Gray, Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer 9, 28-39 (2009).
3. H. Davies, G. R. Bignell, C. Cox, P. Stephens, S. Edkins, S. Clegg, J. Teague, H. Woffendin, M. J. Garnett, W. Bottomley, N. Davis, E. Dicks, R. Ewing, Y. Floyd, K. Gray, S. Hall, R. Hawes, J. Hughes, V. Kosmidou, A. Menzies, C. Mould, A. Parker, C. Stevens, S. Watt, S. Hooper, R. Wilson, H. Jayatilake, B. A. Gusterson, C. Cooper, J. Shipley, D. Hargrave, K. Pritchard-Jones, N. Maitland, G. Chenevix-Trench, G. J. Riggins, D. D. Bigner, G. Palmieri, A. Cossu, A. Flanagan, A. Nicholson, J. W. Ho, S. Y. Leung, S. T. Yuen, B. L. Weber, H. F. Seigler, T. L. Darrow, H. Paterson, R. Marais, C. J. Marshall, R. Wooster, M. R. Stratton, P. A. Futreal, Mutations of the BRAF gene in human cancer. Nature 417, 949-954 (2002).
4. V. Gray-Schopfer, C. Wellbrock, R. Marais, Melanoma biology and new targeted therapy. Nature 445, 851-857 (2007).
5. K. P. Hoeflich, D. C. Gray, M. T. Eby, J. Y. Tien, L. Wong, J. Bower, A. Gogineni, J. Zha, M. J. Cole, H. M. Stern, L. J. Murray, D. P. Davis, S. Seshagiri, Oncogenic BRAF is required for tumor growth and maintenance in melanoma models. Cancer Res. 66, 999-1006 (2006).
6. M. Karasarides, A. Chiloeches, R. Hayward, D. Niculescu-Duvaz, I. Scanlon, F. Friedlos, L. Ogilvie, D. Hedley, J. Martin, C. J. Marshall, C. J. Springer, R. Marais, B-RAF is a therapeutic target in melanoma. Oncogene 23, 6292-6298 (2004).
7. C. Wellbrock, M. Karasarides, R. Marais, The RAF proteins take centre stage. Nat. Rev. Mol. Cell Biol. 5, 875-885 (2004).
8. C. J. Marshall, Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179-185 (1995).
9. http://www.sanger.ac.uk/genetics/CGP/cosmic/.
10. V599EB-RAF is an oncogene in melanocytes. Cancer Res. 64, 2338-2342 (2004).
11. T. Ikenoue, Y. Hikiba, F. Kanai, J. Aragaki, Y. Tanaka, J. Imamura, T. Imamura, M. Ohta, H. Ijichi, K. Tateishi, T. Kawakami, M. Matsumura, T. Kawabe, M. Omata, Different effects of point mutations within the B-Raf glycine-rich loop in colorectal tumors on mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase and nuclear factor κB pathway and cellular transformation. Cancer Res. 64, 3428-3435 (2004).
12. A. J. King, D. R. Patrick, R. S. Batorsky, M. L. Ho, H. T. Do, S. Y. Zhang, R. Kumar, D. W. Rusnak, A. K. Takle, D. M. Wilson, E. Hugger, L. Wang, F. Karreth, J. C. Lougheed, J. Lee, D. Chau, T. J. Stout, E. W. May, C. M. Rominger, M. D. Schaber, L. Luo, A. S. Lakdawala, J. L. Adams, R. G. Contractor, K. S. Smalley, M. Herlyn, M. M. Morrissey, D. A. Tuveson, P. S. Huang, Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res. 66, 11100-11105 (2006).
13. J. Tsai, J. T. Lee, W. Wang, J. Zhang, H. Cho, S. Mamo, R. Bremer, S. Gillette, J. Kong, N. K. Haass, K. Sproesser, L. Li, K. S. Smalley, D. Fong, Y. L. Zhu, A. Marimuthu, H. Nguyen, B. Lam, J. Liu, I. Cheung, J. Rice, Y. Suzuki, C. Luu, C. Settachatgul, R. Shellooe, J. Cantwell, S. H. Kim, J. Schlessinger, K. Y. Zhang, B. L. West, B. Powell, G. Habets, C. Zhang, P. N. Ibrahim, P. Hirth, D. R. Artis, M. Herlyn, G. Bollag, Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc. Natl. Acad. Sci. U.S.A. 105, 3041-3046 (2008).
14. S. M. Wilhelm, C. Carter, L. Tang, D. Wilkie, A. McNabola, H. Rong, C. Chen, X. Zhang, P. Vincent, M. McHugh, Y. Cao, J. Shujath, S. Gawlak, D. Eveleigh, B. Rowley, L. Liu, L. Adnane, M. Lynch, D. Auclair, I. Taylor, R. Gedrich, A. Voznesensky, B. Riedl, L. E. Post, G. Bollag, P. A. Trail, BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64, 7099-7109 (2004).
15. P. T. Wan, M. J. Garnett, S. M. Roe, S. Lee, D. Niculescu-Duvaz, V. M. Good, C. M. Jones, C. J. Marshall, C. J. Springer, D. Barford, R. Marais; Cancer Genome Project, Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855-867 (2004).
16. T. Eisen, T. Ahmad, K. T. Flaherty, M. Gore, S. Kaye, R. Marais, I. Gibbens, S. Hackett, M. James, L. M. Schuchter, K. L. Nathanson, C. Xia, R. Simantov, B. Schwartz, M. Poulin-Costello, P. J. O'Dwyer, M. J. Ratain, Sorafenib in advanced melanoma: A Phase II randomised discontinuation trial analysis. Br. J. Cancer 95, 581-586 (2006).
17. M. J. Ratain, T. Eisen, W. M. Stadler, K. T. Flaherty, S. B. Kaye, G. L. Rosner, M. Gore, A. A. Desai, A. Patnaik, H. Q. Xiong, E. Rowinsky, J. L. Abbruzzese, C. Xia, R. Simantov, B. Schwartz, P. J. O'Dwyer, Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 24, 2505-2512 (2006).
18. R. C. Kane, A. T. Farrell, H. Saber, S. Tang, G. Williams, J. M. Jee, C. Liang, B. Booth, N. Chidambaram, D. Morse, R. Sridhara, P. Garvey, R. Justice, R. Pazdur, Sorafenib for the treatment of advanced renal cell carcinoma. Clin. Cancer Res. 12, 7271-7278 (2006).
19. L. Lang, FDA approves sorafenib for patients with inoperable liver cancer. Gastroenterology 134, 379 (2008).
20. S. V. Madhunapantula, G. P. Robertson, Is B-Raf a good therapeutic target for melanoma and other malignancies? Cancer Res. 68, 5-8 (2008).
21. K. S. Smalley, K. T. Flaherty, Integrating BRAF/MEK inhibitors into combination therapy for melanoma. Br. J. Cancer 100, 431-435 (2009).
22. D. Stuart, K. Aardalen, E. Venetsanakos, T. Nagel, M. Wallroth, D. Batt, S. Ramurthy, D. Poon, M. Faure, E. Lorenzana, F. Salangsang, J. Dove, E. Garrett, M. Aikawa, A. Kaplan, P. Amiri, P. Renhowe, RAF265 is a potent Raf kinase inhibitor with selective anti-proliferative activity in vitro and in vivo. AACR Meet. Abstr. 2008, 4876 (2008).
23. H. Daub, K. Specht, A. Ullrich, Strategies to overcome resistance to targeted protein kinase inhibitors. Nat. Rev. Drug Discov. 3, 1001-1010 (2004).
24. Y. Liu, N. S. Gray, Rational design of inhibitors that bind to inactive kinase conformations. Nat. Chem. Biol. 2, 358-364 (2006).
25. http://www.ccdc.cam.ac.uk/products/life-sciences/gold/.
26. R. Palacios, M. Steinmetz, IL3-dependent mouse clones that express B-220 surface antigen, contain Ig genes in germ-line configuration, and generate B lymphocytes in vivo. Cell 41, 727-734 (1985).
27. M. J. Garnett, R. Marais, Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6, 313-319 (2004).
28. M. E. Gorre, M. Mohammed, K. Ellwood, N. Hsu, R. Paquette, P. N. Rao, C. L. Sawyers, Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876-880 (2001).
29. W. Pao, V. A. Miller, K. A. Politi, G. J. Riely, R. Somwar, M. F. Zakowski, M. G. Kris, H. Varmus, Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2, e73 (2005).
30. C. H. Yun, K. E. Mengwasser, A. V. Toms, M. S. Woo, H. Greulich, K. K. Wong, M. Meyerson, M. J. Eck, The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl. Acad. Sci. U.S.A. 105, 2070-2075 (2008).
31. K. Flaherty, I. Puzanov, J. Sosman, K. Kim, A. Ribas, G. McArthur, R. J. Lee, J. F. Grippo, K. Nolop, P. Chapman, Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. J. Clin. Oncol. (Meet. Abstr.) 27, 9000 (2009).
32. G. K. Schwartz, S. Robertson, A. Shen, E. Wang, L. Pace, H. Dials, D. Mendelson, P. Shannon, M. Gordon, A phase I study of XL281, a selective oral RAF kinase inhibitor, in patients (Pts) with advanced solid tumors. J. Clin. Oncol. (Meet. Abstr.) 27, 3513 (2009).
33. H. Kantarjian, C. Sawyers, A. Hochhaus, F. Guilhot, C. Schiffer, C. Gambacorti-Passerini, D. Niederwieser, D. Resta, R. Capdeville, U. Zoellner, M. Talpaz, B. Druker, J. Goldman, S. G. O'Brien, N. Russell, T. Fischer, O. Ottmann, P. Cony-Makhoul, T. Facon, R. Stone, C. Miller, M. Tallman, R. Brown, M. Schuster, T. Loughran, A. Gratwohl, F. Mandelli, G. Saglio, M. Lazzarino, D. Russo, M. Baccarani, E. Morra; International STI571 CML Study Group, Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N. Engl. J. Med. 346, 645-652 (2002).
34. C. L. Sawyers, A. Hochhaus, E. Feldman, J. M. Goldman, C. B. Miller, O. G. Ottmann, C. A. Schiffer, M. Talpaz, F. Guilhot, M. W. Deininger, T. Fischer, S. G. O'Brien, R. M. Stone, C. B. Gambacorti-Passerini, N. H. Russell, J. J. Reiffers, T. C. Shea, B. Chapuis, S. Coutre, S. Tura, E. Morra, R. A. Larson, A. Saven, C. Peschel, A. Gratwohl, F. Mandelli, M. Ben-Am, I. Gathmann, R. Capdeville, R. L. Paquette, B. J. Druker, Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: Results of a phase II study. Blood 99, 3530-3539 (2002).
35. M. Talpaz, R. T. Silver, B. J. Druker, J. M. Goldman, C. Gambacorti-Passerini, F. Guilhot, C. A. Schiffer, T. Fischer, M. W. Deininger, A. L. Lennard, A. Hochhaus, O. G. Ottmann, A. Gratwohl, M. Baccarani, R. Stone, S. Tura, F. X. Mahon, S. Fernandes-Reese, I. Gathmann, R. Capdeville, H. M. Kantarjian, C. L. Sawyers, Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: Results of a phase 2 study. Blood 99, 1928-1937 (2002).
36. E. Tamborini, L. Bonadiman, A. Greco, V. Albertini, T. Negri, A. Gronchi, R. Bertulli, M. Colecchia, P. G. Casali, M. A. Pierotti, S. Pilotti, A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 127, 294-299 (2004).
37. I. Niculescu-Duvaz, E. Roman, S. R. Whittaker, F. Friedlos, R. Kirk, I. J. Scanlon, L. C. Davies, D. Niculescu-Duvaz, R. Marais, C. J. Springer, Novel inhibitors of B-RAF based on a disubstituted pyrazine scaffold. Generation of a nanomolar lead. J. Med. Chem. 49, 407-416 (2006).
38. R. Marais, Y. Light, H. F. Paterson, C. S. Mason, C. J. Marshall, Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic Ras and tyrosine kinases. J. Biol. Chem. 272, 4378-4383 (1997).
39. C. S. Mason, C. J. Springer, R. G. Cooper, G. Superti-Furga, C. J. Marshall, R. Marais, Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. EMBO J. 18, 2137-2148 (1999).
40. S. R. Whittaker, M. I. Walton, M. D. Garrett, P. Workman, The cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) inhibits retinoblastoma protein phosphorylation, causes loss of cyclin D1, and activates the mitogen-activated protein kinase pathway. Cancer Res. 64, 262-272 (2004).
41. J. Wang, R. M. Wolf, J. W. Caldwell, P. A. Kollman, D. A. Case, Development and testing of a general amber force field. J. Comput. Chem. 25, 1157-1174 (2004).
42. G. Jones, P. Willett, R. C. Glen, A. R. Leach, R. Taylor, Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol. 267, 727-748 (1997).
43. P. Workman, A. Balmain, J. A. Hickman, N. J. McNally, A. M. Rohas, N. A. Mitchison, C. G. Pierrepoint, R. Raymond, C. Rowlatt, T. C. Stephens, J. Wallace, UKCCCR guidelines for the welfare of animals in experimental neoplasia. Lab. Anim. 22, 195-201 (1988).
44. N. Dhomen, J. S. Reis-Filho, S. da Rocha Dias, R. Hayward, K. Savage, V. Delmas, L. Larue, C. Pritchard, R. Marais, Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell 15, 294-303 (2009).
45. National Centre for Protein Kinase Profiling, University of Dundee, Dundee, UK.
46. Funding: Wellcome Trust (refs: 071487/Z/03/A and 080333/Z/06/Z), Cancer Research UK (refs: C309/A2187, C107/A3096, and C107/A10433), Institute of Cancer Research, and Isle of Man Anti-Cancer Association. Author contributions: S.W. and R.M. conceived, designed, and analyzed the data; S.W., R.K., R.H., A.A., N.C., and A.V. performed the biological experiments; A.N., D.N.-D., and C.S. synthesized the drugs; C.S. and R.M. provided funding; and S.W., A.Z., C.S., and R.M. wrote the manuscript. Competing interests: The authors have no competing interests.