BRAF as a target for cancer therapy

Anti-Cancer Agents in Medicinal Chemistry

Volumn 11, Issue 3, 2011, Pages 285-295

  Dienstmann, Rodrigo ^a   Tabernero, Josep ^a  

^a HOSPITAL UNIVERSITARI VALL D HEBRON   (Spain)

Author keywords

BRAF inhibitor; BRAF V600; Melanoma; RAF inhibitor; Resistance; Targeted therapy

Indexed keywords

ARQ 736; B RAF KINASE; B RAF KINASE INHIBITOR; BKM 120; BMS 908662; CHIR 265; GDC 0973; GSK 1120212; GSK 2118436; GSKL 2118436; KI 67 ANTIGEN; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PLX 4032; PLX 4720; PROTEIN KINASE B; RO 5126766; RO 5185426; RO 5212054; SELUMETINIB; SORAFENIB; UNCLASSIFIED DRUG; XL 281;

ALOPECIA; ANOREXIA; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTHRALGIA; BLOOD TOXICITY; BLURRED VISION; CANCER RESISTANCE; CANCER THERAPY; CENTRAL SEROUS RETINOPATHY; CHEMOTHERAPY INDUCED EMESIS; COLORECTAL CANCER; DIARRHEA; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG ERUPTION; DRUG FEVER; DRUG INDUCED CANCER; DRUG INDUCED HEADACHE; DRUG TARGETING; ENZYME ACTIVATION; FATIGUE; GENE MUTATION; HAND FOOT SYNDROME; HUMAN; HYPERTENSION; KERATOACANTHOMA; MELANOMA; METASTASIS; MUCOSA INFLAMMATION; NAUSEA; NONHUMAN; ONCOGENE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHOTOSENSITIVITY; REVIEW; SIDE EFFECT; SKIN CARCINOMA; SOLID TUMOR; SQUAMOUS CELL CARCINOMA; THYROID PAPILLARY CARCINOMA;

EID: 79954507333     PISSN: 18715206     EISSN: None     Source Type: Journal    
DOI: 10.2174/187152011795347469     Document Type: Review

References (91)

1. Davies, H.; Bignell, G.R.; Cox, C.; Stephens, P.; Edkins, S.; Clegg, S.; Teague, J.; Woffendin, H.; Garnett, M.J.; Bottomley, W.; Davis, N.; Dicks, E.; Ewing, R.; Floyd, Y.; Gray, K.; Hall, S.; Hawes, R.; Hughes, J.; Kosmidou, V.; Menzies, A.; Mould, C.; Parker, A.; Stevens, C.; Watt, S.; Hooper, S.; Wilson, R.; Jayatilake, H.; Gusterson, B.A.; Cooper, C.; Shipley, J.; Hargrave, D.; Pritchard-Jones, K.; Maitland, N.; Chenevix-Trench, G.; Riggins, G.J.; Bigner, D.D.; Palmieri, G.; Cossu, A.; Flanagan, A.; Nicholson, A.; Ho, J.W.; Leung, S.Y.; Yuen, S.T.; Weber, B.L.; Seigler, H.F.; Darrow, T.L.; Paterson, H.; Marais, R.; Marshall, C.J.; Wooster, R.; Stratton, M.R.; Futreal, P.A. Mutations of the BRAF gene in human cancer. Nature, 2002, 417(6892), 949-954.
2. Martin, G.S. Cell signaling and cancer. Cancer Cell, 2003, 4(3), 167-174.
3. Zhang, X.D.; Borrow, J.M.; Zhang, X.Y.; Nguyen, T.; Hersey, P. Activation of ERK1/2 protects melanoma cells from TRAILinduced apoptosis by inhibiting Smac/DIABLO release from mitochondria. Oncogene, 2003, 22(19), 2869-2881.
4. Zhuang, L.; Lee, C.S.; Scolyer, R.A.; McCarthy, S.W.; Palmer, A.A.; Zhang, X.D.; Thompson, J.F.; Bron, L.P.; Hersey, P. Activation of the extracellular signal regulated kinase (ERK) pathway in human melanoma. J. Clin. Pathol., 2005, 58(11), 1163-1169.
5. Garnett, M.J.; Marais, R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell, 2004, 6(4), 313-319.
6. Flaherty, K.T.; McArthur, G. BRAF, a target in melanoma: implications for solid tumor drug development. Cancer, 2010, 116(21), 4902-4913.
7. Arkenau, H.T.; Kefford, R.; Long, G.V. Targeting BRAF for patients with melanoma. Br. J. Cancer, 2010, Dec 7. [Epub ahead of print]
8. Bamford, S.; Dawson, E.; Forbes, S.; Clements, J.; Pettett, R.; Dogan, A.; Flanagan, A.; Teague, J.; Futreal, P.A.; Stratton, M.R.; Wooster, R. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br. J. Cancer, 2004, 91(2), 355-358.
9. Gorden, A.; Osman, I.; Gai, W.; He, D.; Huang, W.; Davidson, A.; Houghton, A.N.; Busam, K.; Polsky, D. Analysis of BRAF and NRAS mutations in metastatic melanoma tissues. Cancer Res., 2003, 63(14), 3955-3957.
10. Cohen, Y.; Xing, M.; Mambo, E.; Guo, Z.; Wu, G.; Trink, B.; Beller, U.; Westra, W.H.; Ladenson, P.W.; Sidransky, D. BRAF mutation in papillary thyroid carcinoma. J. Natl. Cancer Inst., 2003, 95(8), 625-627.
11. Nikiforova, M.N.; Kimura, E.T.; Gandhi, M.; Biddinger, P.W.; Knauf, J.A.; Basolo, F.; Zhu, Z.; Giannini, R.; Salvatore, G.; Fusco, A.; Santoro, M.; Fagin, J.A.; Nikiforov, Y.E. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J. Clin. Endocrinol. Metab., 2003, 88(11), 5399-5404.
12. Samowitz, W.S.; Sweeney, C.; Herrick, J.; Albertsen, H.; Levin, T.R.; Murtaugh, M.A.; Wolff, R.K.; Slattery, M.L. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res., 2005, 65(14), 6063-6069.
13. Tol, J.; Nagtegaal, I.D.; Punt, C.J. BRAF mutation in metastatic colorectal cancer. N. Engl. J. Med., 2009, 361(1), 98-99.
14. De Roock, W.; Claes, B.; Bernasconi, D.; De Schutter, J.; Biesmans, B.; Fountzilas, G.; Kalogeras, K.T.; Kotoula, V.; Papamichael, D.; Laurent-Puig, P.; Penault-Llorca, F.; Rougier, P.; Vincenzi, B.; Santini, D.; Tonini, G.; Cappuzzo, F.; Frattini, M.; Molinari, F.; Saletti, P.; De Dosso, S.; Martini, M.; Bardelli, A.; Siena, S.; Sartore-Bianchi, A.; Tabernero, J.; Macarulla, T.; Di Fiore, F.; Gangloff, A.O.; Ciardiello, F.; Pfeiffer, P.; Qvortrup, C.; Hansen, T.P.; Van Cutsem, E.; Piessevaux, H.; Lambrechts, D.; Delorenzi, M.; Tejpar, S. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol., 2010, 11(8), 753-762.
15. Singer, G.; Oldt, R. 3rd.; Cohen, Y.; Wang, B.G.; Sidransky, D.; Kurman, R.J.; Shih, IeM. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J. Natl. Cancer Inst., 2003, 95(6), 484-486.
16. Tannapfel, A.; Sommerer, F.; Benicke, M.; Katalinic, A.; Uhlmann, D.; Witzigmann, H.; Hauss, J.; Wittekind, C. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut, 2003, 52(5), 706-712.
17. Cho, N.Y.; Choi, M.; Kim, B.H.; Cho, Y.M.; Moon, K.C.; Kang, G.H. BRAF and KRAS mutations in prostatic adenocarcinoma. Int. J. Cancer, 2006, 119(8), 1858-1862.
18. Honecker, F.; Wermann, H.; Mayer, F.; Gillis, A.J.; Stoop, H.; van Gurp, R.J.; Oechsle, K.; Steyerberg, E.; Hartmann, J.T.; Dinjens, W.N.; Oosterhuis, J.W.; Bokemeyer, C.; Looijenga, L.H. Microsatellite instability, mismatch repair deficiency, and BRAF mutation in treatment-resistant germ cell tumors. J. Clin. Oncol., 2009, 27(13), 2129-2136.
19. Curtin, J.A.; Fridlyand, J.; Kageshita, T.; Patel, H.N.; Busam, K.J.; Kutzner, H.; Cho, K.H.; Aiba, S.; Bröcker, E.B.; LeBoit, P.E.; Pinkel, D.; Bastian, B.C. Distinct sets of genetic alterations in melanoma. N. Engl. J. Med., 2005, 353(20), 2135-2147.
20. Pollock, P.M.; Harper, U.L.; Hansen, K.S.; Yudt, L.M.; Stark, M.; Robbins, C.M.; Moses, T.Y.; Hostetter, G.; Wagner, U.; Kakareka, J.; Salem, G.; Pohida, T.; Heenan, P.; Duray, P.; Kallioniemi, O.; Hayward, N.K.; Trent, J.M.; Meltzer, P.S. High frequency of BRAF mutations in nevi. Nat. Genet., 2003, 33(1), 19-20.
21. Uribe, P.; Wistuba, II; Gonzalez, S. BRAF mutation: a frequent event in benign, atypical, and malignant melanocytic lesions of the skin. Am. J. Dermatopathol., 2003, 25(5), 365-370.
22. Liu, W.; Kelly, J.W.; Trivett, M.; Murray, W.K.; Dowling, J.P.; Wolfe, R.; Mason, G.; Magee, J.; Angel, C.; Dobrovic, A.; McArthur, G.A. Distinct clinical and pathological features are associated with the BRAFT1799A(V600E) mutation in primary melanoma. J. Invest. Dermatol., 2007, 127(4), 900-905.
23. Thomas, N.E.; Edmiston, S.N.; Alexander, A.; Millikan, R.C.; Groben, P.A.; Hao, H.; Tolbert, D.; Berwick, M.; Busam, K.; Begg, C.B.; Mattingly, D.; Ollila, D.W.; Tse, C.K.; Hummer, A.; Lee-Taylor, J.; Conway, K. Number of nevi and early-life ambient UV exposure are associated with BRAF-mutant melanoma. Cancer Epidemiol. Biomarkers Prev., 2007, 16(5), 991-997.
24. Houben, R.; Becker, J.C.; Kappel, A.; Terheyden, P.; Brocker, E.B.; Goetz, R.; Rapp, U.R. Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. J. Carcinog., 2004, 3(1), 6.
25. Ugurel, S.; Thirumaran, R.K.; Bloethner, S.; Gast, A.; Sucker, A.; Mueller-Berghaus, J.; Rittgen, W.; Hemminki, K.; Becker, J.C.; Kumar, R.; Schadendorf, D. B-RAF and N-RAS mutations are preserved during short time in vitro propagation and differentially impact prognosis. PLoS One, 2007, 2(2), e236.
26. Shinozaki, M.; Fujimoto, A.; Morton, D.L.; Hoon, D.S.B. Incidence of BRAF Oncogene mutation and clinical relevance for primary cutaneous melanomas. Clin. Cancer Res., 2004, 10(5), 1753-1755.
27. van't Veer, L.J.; Burgering, B.M.; Versteeg, R.; Boot, A.J.; Ruiter, D.J.; Osanto, S.; Schrier, P.I.; Bos, J.L. N-ras mutations in human cutaneous melanoma from sun-exposed body sites. Mol. Cell Biol., 1989, 9(7), 3114-3116.
28. Tsao, H.; Goel, V.; Wu, H.; Yang, G.; Haluska, F.G. Genetic interaction between NRAS and BRAF mutations and PTEN/ MMAC1 inactivation in melanoma. J. Invest. Dermatol., 2004, 122(2), 337-341.
29. Goel, V.K.; Lazar, A.J.; Warneke, C.L.; Redston, M.S.; Haluska, F.G. Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J. Invest. Dermatol., 2006, 126(1), 154-160.
30. Curtin, J.A.; Busam, K.; Pinkel, D.; Bastian, B.C. Somatic activation of KIT in distinct subtypes of melanoma. J. Clin. Oncol., 2006, 24(26), 4340-4346.
31. Dai, D.L.; Martinka, M.; Li, G. Prognostic significance of activated Akt expression in melanoma: a clinicopathologic study of 292 cases. J. Clin. Oncol., 2005, 23(7), 1473-1482.
32. Cheung, M.; Sharma, A.; Madhunapantula, S.V.; Robertson, G.P. Akt3 and mutant V600E B-Raf cooperate to promote early melanoma development. Cancer Res., 2008, 68(9), 3429-3439.
33. Fukushima, T.; Suzuki, S.; Mashiko, M.; Ohtake, T.; Endo, Y.; Takebayashi, Y.; Sekikawa, K.; Hagiwara, K.; Takenoshita, S. BRAF mutations in papillary carcinomas of the thyroid. Oncogene, 2003, 22(41), 6455-6457.
34. Kimura, E.T.; Nikiforova, M.N.; Zhu, Z.; Knauf, J.A.; Nikiforov, Y.E.; Fagin, J.A. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res., 2003, 63(7), 1454-1457.
35. Rosenbaum, E.; Hosler, G.; Zahurak, M.; Cohen, Y.; Sidransky, D.; Westra, W.H. Mutational activation of BRAF is not a major event in sporadic childhood papillary thyroid carcinoma. Mod. Pathol., 2005, 18(7), 898-902.
36. O'Neill, C.J.; Bullock, M.; Chou, A.; Sidhu, S.B.; Delbridge, L.W.; Robinson, B.G.; Gill, A.J.; Learoyd, D.L.; Clifton-Bligh, R.; Sywak, M.S. BRAF(V600E) mutation is associated with an increased risk of nodal recurrence requiring reoperative surgery in patients with papillary thyroid cancer. Surgery, 2010, 148(6), 1139-45.
37. Beach, R.; Chan, A.O.; Wu, T.T.; White, J.A.; Morris, J.S.; Lunagomez, S.; Broaddus, R.R.; Issa, J.P.; Hamilton, S.R.; Rashid, A. BRAF mutations in aberrant crypt foci and hyperplastic polyposis. Am. J. Pathol., 2005, 166(4), 1069-1075.
38. Oliveira, C.; Pinto, M.; Duval, A.; Brennetot, C.; Domingo, E.; Espín, E.; Armengol, M.; Yamamoto, H.; Hamelin, R.; Seruca, R.; Schwartz, S. Jr. BRAF mutations characterize colon but not gastric cancer with mismatch repair deficiency. Oncogene, 2003, 22(57), 9192-9196.
39. Velho, S.; Oliveira, C.; Ferreira, A.; Ferreira, A.C.; Suriano, G.; Schwartz, S. Jr.; Duval, A.; Carneiro, F.; Machado, J.C.; Hamelin, R.; Seruca, R. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur. J. Cancer, 2005, 41(11), 1649-1654.
40. French, A.J.; Sargent, D.J.; Burgart, L.J.; Burgart, L.J.; Foster, N.R.; Kabat, B.F.; Goldberg, R.; Shepherd, L.; Windschitl, H.E.; Thibodeau, S.N. Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin. Cancer Res., 2008, 14(11), 3408-3415.
41. Ogino, S.; Nosho, K.; Kirkner, G.J.; Kawasaki, T.; Meyerhardt, J.A.; Loda, M.; Giovannucci, E.L.; Fuchs, C.S. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut, 2009, 58(1), 90-96.
42. Weinstein, I.B.; Begemann, M.; Zhou, P.; Han, E.K.; Sgambato, A.; Doki, Y.; Arber, N.; Ciaparrone, M.; Yamamoto, H. Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and therapy. Clin. Cancer Res., 1997, 3(12 Pt 2), 2696-2702.
43. Wan, P.T.; Garnett, M.J.; Roe, S.M.; Lee, S.; Niculescu-Duvaz, D.; Good, V.M.; Jones, C.M.; Marshall, C.J.; Springer, C.J.; Barford, D.; Marais, R.; Cancer Genome Project. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of BRAF. Cell, 2004, 116(6), 855-867.
44. Calipel, A.; Lefevre, G.; Pouponnot, C.; Mouriaux, F.; Eychene, A.; Mascarelli F. Mutation in B-Raf in human choroidal melanoma cell lines mediates cell proliferation and transformation through the MEK/ERK pathway. J. Biol. Chem., 2003, 278(43), 42409-42418.
45. Karasarides, M.; Chiloeches, A.; Hayward, R.; Niculescu-Duvaz, D.; Scanlon, I.; Friedlos, F.; Ogilvie, L.; Hedley, D.; Martin, J.; Marshall, C.J.; Springer, C.J.; Marais, R. B-RAF is a therapeutic target in melanoma. Oncogene, 2004, 23(37), 6292-6298.
46. Hingorani, S.R.; Jacobetz, M.A.; Robertson, G.P.; Herlyn, M.; Tuveson, D.A. Suppression of BRAF(V599E) in human melanoma abrogates transformation. Cancer Res., 2003, 63(17), 5198-5202.
47. Sumimoto, H.; Miyagishi, M.; Miyoshi, H.; Yamagata, S.; Shimizu, A.; Taira, K.; Kawakami, Y. Inhibition of growth and invasive ability of melanoma by inactivation of mutated BRAF with lentivirus-mediated RNA interference. Oncogene, 2004, 23(36), 6031-6039.
48. Stahl, J.M.; Cheung, M.; Sharma, A.; Trivedi, N.R.; Shanmugam, S.; Robertson, G.P. Loss of PTEN promotes tumor development in malignant melanoma. Cancer Res., 2003, 63(11), 2881-2890.
49. Dankort, D.; Curley, D.P.; Cartlidge, R.A.; Nelson, B.; Karnezis, A.N.; Damsky, W.E. Jr.; You, M.J.; DePinho, R.A.; McMahon, M.; Bosenberg, M. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat. Genet., 2009, 41(5), 544-552.
50. Sharma, S.V.; Settleman, J. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev., 2007, 21(24), 3214-3231.
51. Wilhelm, S.M.; Carter, C.; Tang, L.; Wilkie, D.; McNabola, A.; Rong, H.; Chen, C.; Zhang, X.; Vincent, P.; McHugh, M.; Cao, Y.; Shujath, J.; Gawlak, S.; Eveleigh, D.; Rowley, B.; Liu, L.; Adnane, L.; Lynch, M.; Auclair, D.; Taylor, I.; Gedrich, R.; Voznesensky, A.; Riedl, B.; Post, L.E.; Bollag, G.; Trail, P.A. 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., 2004, 64(19), 7099-7109.
52. Eisen, T.; Ahmad, T.; Flaherty, K.T.; Gore, M.; Kaye, S.; Marais, R.; Gibbens, I.; Hackett, S.; James, M.; Schuchter, L.M.; Nathanson, K.L.; Xia, C.; Simantov, R.; Schwartz, B.; Poulin-Costello, M.; O'Dwyer, P.J.; Ratain, M.J. Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br. J. Cancer, 2006, 95(5), 581-586.
53. Hauschild, A.; Agarwala, S.S.; Trefzer, U.; Hogg, D.; Robert, C.; Hersey, P.; Eggermont, A.; Grabbe, S.; Gonzalez, R.; Gille, J.; Peschel, C.; Schadendorf, D.; Garbe, C.; O'Day, S.; Daud, A.; White, J.M.; Xia, C.; Patel, K.; Kirkwood, J.M.; Keilholz, U. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J. Clin. Oncol., 2009, 27(17), 2823-2830.
54. Ott, P.A.; Hamilton, A.; Min, C.; Safarzadeh-Amiri, S.; Goldberg, L.; Yoon, J.; Yee, H.; Buckley, M.; Christos, P.J.; Wright, J.J.; Polsky, D.; Osman, I.; Liebes, L.; Pavlick, A.C. A Phase II trial of sorafenib in metastatic melanoma with tissue correlates. PLoS One, 2010, 5(12), e15588.
55. Ramurthy, S.; Subramanian, S.; Aikawa, M.; Amiri, P.; Costales, A.; Dove, J.; Fong, S.; Jansen, J.M.; Levine, B.; Ma, S.; McBride, C.M.; Michaelian, J.; Pick, T.; Poon, D.J.; Girish, S.; Shafer, C.M.; Stuart, D.; Sung, L.; Renhowe, P.A. Design and synthesis of orally bioavailable benzimidazoles as Raf kinase inhibitors. J. Med. Chem., 2008, 51(22), 7049-7052.
56. Hoeflich, K.P.; Herter, S.; Tien, J.; Wong, L.; Berry, L.; Chan, J.; O'Brien, C.; Modrusan, Z.; Seshagiri, S., Lackner, M.; Stern, H.; Choo, E.; Murray, L.; Friedman, L.S.; Belvin, M. Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signalregulated kinase/mitogen-activated protein kinase pathway suppression. Cancer Res., 2009, 69(7), 3042-3051.
57. Montagut, C.; Sharma, S.V.; Shioda, T.; McDermott, U.; Ulman, M.; Ulkus, L.E.; Dias-Santagata, D.; Stubbs, H.; Lee, D.Y.; Singh, A.; Drew, L.; Haber, D.A.; Settleman, J. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res., 2008, 68(12), 4853-4861.
58. Whittaker, S.; Ménard, D.; Kirk, R.; Ogilvie, L.; Hedley, D.; Zambon, A.; Lopes, F.; Preece, N.; Manne, H.; Rana, S.; Lambros, M.; Reis-Filho, J.S.; Marais, R.; Springer, C.J. A novel, selective, and efficacious nanomolar pyridopyrazinone inhibitor of V600EBRAF. Cancer Res., 2010, 70(20), 8036-8044.
59. Tsai, J.; Lee, J.T.; Wang, W.; Zhang, J.; Cho, H.; Mamo, S.; Bremer, R.; Gillette, S.; Kong, J.; Haass, N.K.; Sproesser, K.; Li, L.; Smalley, K.S.; Fong, D.; Zhu, Y.L.; Marimuthu, A.; Nguyen, H.; Lam, B.; Liu, J.; Cheung, I.; Rice, J.; Suzuki, Y.; Luu, C.; Settachatgul, C.; Shellooe, R.; Cantwell, J.; Kim, S.H.; Schlessinger, J.; Zhang, K.Y.; West, B.L.; Powell, B.; Habets, G.; Zhang, C.; Ibrahim, P.N.; Hirth, P.; Artis, D.R.; Herlyn, M.; Bollag, G. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc. Natl. Acad. Sci. USA, 2008, 105(8), 3041-3046.
60. Yang, H.; Higgins, B.; Kolinsky, K.; Packman, K.; Go, Z.; Iyer, R.; Kolis, S.; Zhao, S.; Lee, R.; Grippo, J.F.; Schostack, K.; Simcox, M.E.; Heimbrook, D.; Bollag, G.; Su, F. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res., 2010, 70(13), 5518-5527.
61. Khazak, V.; Astsaturov, I.; Serebriiskii, I.G.; Golemis, E.A. Selective Raf inhibition in cancer therapy. Expert Opin. Ther. Targets, 2007, 11(12), 1587-1609.
62. Joseph, E.W.; Pratilas, C.A.; Poulikakos, P.I.; Tadi, M.; Wang, W.; Taylor, B.S.; Halilovic, E.; Persaud, Y.; Xing, F.; Viale, A.; Tsai, J.; Chapman, P.B.; Bollag, G.; Solit, D.B.; Rosen, N. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc. Natl. Acad. Sci. USA, 2010, 107(33), 14903-14908.
63. Sondergaard, J.N.; Nazarian, R.; Wang, Q.; Guo, D.; Hsueh, T.; Mok, S.; Sazegar, H.; MacConaill, L.E.; Barretina, J.G.; Kehoe, S.M.; Attar, N.; von Euw, E.; Zuckerman, J.E.; Chmielowski, B.; Comin-Anduix, B.; Koya, R.C.; Mischel, P.S.; Lo, R.S.; Ribas, A. Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. J. Transl. Med., 2010, 8, 39.
64. Halaban, R.; Zhang, W.; Bacchiocchi, A.; Cheng, E.; Parisi, F.; Ariyan, S.; Krauthammer, M.; McCusker, J.P.; Kluger, Y.; Sznol, M. PLX4032, a selective BRAF (V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells. Pigment Cell Melanoma Res., 2010, 23(2), 190-200.
65. Sala, E.; Mologni, L.; Truffa, S.; Gaetano, C.; Bollag, G.E.; Gambacorti-Passerini, C. BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol. Cancer. Res., 2008, 6(5), 751-759.
66. Hatzivassiliou, G.; Song, K.; Yen, I.; Brandhuber, B.J.; Anderson, D.J.; Alvarado, R.; Ludlam, M.J.; Stokoe, D.; Gloor, S.L.; Vigers, G.; Morales, T.; Aliagas, I.; Liu, B.; Sideris, S.; Hoeflich, K.P.; Jaiswal, B.S.; Seshagiri, S.; Koeppen, H.; Belvin, M.; Friedman, L.S.; Malek, S. et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature, 2010, 464(7287), 431-435.
67. Poulikakos, P.I.; Zhang, C.; Bollag, G.; Shokat, K.M.; Rosen, N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature, 2010, 464(7287), 427-430.
68. Kaplan, F.M.; Shao, Y.; Mayberry, M.M.; Aplin, A.E. Hyperactivation of MEK-ERK1/2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant NRAS melanoma cells. Oncogene, 2011, 30(3), 366-371.
69. Heidorn, S.J.; Milagre, C.; Whittaker, S.; Nourry, A.; Niculescu-Duvas, I.; Dhomen, N.; Hussain, J.; Reis-Filho, J.S.; Springer, C.J.; Pritchard, C.; Marais, R. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell, 2010, 140(2), 209-221.
70. Solit, D.; Rosen, N. Oncogenic RAF: a brief history of time. Pigment Cell Melanoma Res., 2010, 23(6), 760-762.
71. Goydos, J.S., Mann B, Kim HJ, Gabriel EM, Alsina J, Germino FJ, Shih W, Gorski DH. et al. Detection of B-RAF and N-RAS mutations in human melanoma. J. Am. Coll. Surg., 2005, 200(3), 362-370.
72. Flaherty, K.T.; Puzanov, I.; Kim, K.B.; Ribas, A.; McArthur, G.A.; Sosman, J.A.; O'Dwyer, P.J.; Lee, R.J.; Grippo, J.F.; Nolop, K.; Chapman, P.B. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med., 2010, 363(9), 809-819.
73. Bollag, G.; Hirth, P.; Tsai, J.; Zhang, J.; Ibrahim, P.N.; Cho, H.; Spevak, W.; Zhang, C.; Zhang, Y.; Habets, G.; Burton, E.A.; Wong, B.; Tsang, G.; West, B.L.; Powell, B.; Shellooe, R.; Marimuthu, A.; Nguyen, H.; Zhang, K.Y.; Artis, D.R.; Schlessinger, J.; Su, F.; Higgins, B.; Iyer, R.; D'Andrea, K.; Koehler, A.; Stumm, M.; Lin, P.S.; Lee, R.J.; Grippo, J.; Puzanov, I.; Kim, K.B.; Ribas, A.; McArthur, G.A.; Sosman, J.A.; Chapman, P.B.; Flaherty, K.T.; Xu, X.; Nathanson, K.L.; Nolop, K. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature, 2010, 467(7315), 596-599.
74. Rubinstein, J.C.; Sznol, M.; Pavlick, A.C.; Ariyan, S.; Cheng, E.; Bacchiocchi, A.; Kluger, H.M.; Narayan, D.; Halaban, R. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J. Transl. Med., 2010, 8, 67.
75. Arnault, J.P.; Wechsler, J.; Escudier, B.; Spatz, A.; Tomasic, G.; Sibaud, V.; Aractingi, S.; Grange, J.D.; Poirier-Colame, V.; Malka, D.; Soria, J.C.; Mateus, C.; Robert, C. Keratoacanthomas and squamous cell carcinomas in patient receiving sorafenib. J. Clin. Oncol., 2009, 27(23), e59-61.
76. Cichowski, K.; Janne, P.A. Drug discovery: inhibitors that activate. Nature, 2010, 464(7287), 358-359.
77. Spencer, J.M.; Kahn, S.M.; Jiang, W.; DeLeo, V.A.; Weinstein, I.B. Activated ras genes occur in human actinic keratoses, premalignant precursors to squamous cell carcinomas. Arch. Dermatol., 1995, 131(7), 796-800.
78. Roberts, A.; Allanson, J.; Jadico, S.K.; Kavamura, M.I.; Noonan, J.; Opitz, J.M.; Young, T.; Neri, G. The cardiofaciocutaneous syndrome. J. Med. Genet., 2006, 43(11), 833-842.
79. Plexxikon Announces Preliminary PLX4032 Phase 2 Data Confirming Substantial Response Rate in Metastatic Melanoma Patients. http://www.plexxikon.com/view.cfm/83/Press-Releases (Accessed Nov 5, 2011).
80. Plexxikon Reports Overall Survival Benefit for Melanoma Patients in PLX4032 Phase 3 Trial Available in http://www.plexxikon.com/view.cfm/86/Press-Releases (Accessed Jan 18, 2011).
81. Whittaker, S.; Kirk, R.; Hayward, R.; Zambon, A.; Viros, A.; Cantarino, N.; Affolter, A.; Nourry, A.; Niculescu-Duvaz, D.; Springer, C.; Marais, R. Gatekeeper mutations mediate resistance to BRAFtargeted therapies. Sci. Transl. Med., 2010, 2(35), 35ra41.
82. Nazarian, R.; Shi, H.; Wang, Q.; Kong, X.; Koya, R.C.; Lee, H.; Chen, Z.; Lee, M.K.; Attar, N.; Sazegar, H.; Chodon, T.; Nelson, S.F.; McArthur, G.; Sosman, J.A.; Ribas, A.; Lo, R.S. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature, 2010, 468(7326), 973-977.
83. Emery, C.M.; Vijayendran, K.G.; Zipser, M.C.; Sawyer, A.M.; Niu, L.; Kim, J.J.; Hatton, C.; Chopra, R.; Oberholzer, P.A.; Karpova, M.B.; MacConaill, L.E.; Zhang, J.; Gray, N.S.; Sellers, W.R.; Dummer, R.; Garraway, L.A. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc. Natl. Acad. Sci USA, 2009, 106(48), 20411-20416.
84. Johannessen, C.M.; Boehm, J.S.; Kim, S.Y.; Thomas, S.R.; Wardwell, L.; Johnson, L.A.; Emery, C.M.; Stransky, N.; Cogdill, A.P.; Barretina, J.; Caponigro, G.; Hieronymus, H.; Murray, R.R.; Salehi-Ashtiani, K.; Hill, D.E.; Vidal, M.; Zhao, J.J.; Yang, X.; Alkan, O.; Kim, S.; Harris, J.L.; Wilson, C.J.; Myer, V.E.; Finan, P.M.; Root, D.E.; Roberts, T.M.; Golub, T.; Flaherty, K.T.; Dummer, R.; Weber, B.L.; Sellers, W.R.; Schlegel, R.; Wargo, J.A.; Hahn, W.C.; Garraway, L.A. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature, 2010, 468(7326), 968-972.
85. Davies, B.R.; Logie, A.; McKay, J.S.; Martin, P.; Steele, S.; Jenkins, R.; Cockerill, M.; Cartlidge, S.; Smith, P.D. AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol. Cancer Ther., 2007, 6(8), 2209-2219.
86. Solit D.B.; Garraway, L.A.; Pratilas, C.A.; Sawai, A.; Getz, G.; Basso, A.; Ye, Q.; Lobo, J.M.; She, Y.; Osman, I.; Golub, T.R.; Sebolt-Leopold, J.; Sellers, W.R.; Rosen, N. BRAF mutation predicts sensitivity to MEK inhibition. Nature, 2006, 439(7074), 358-362.
87. Smalley, K.S.; Haass, N.K.; Brafford, P.A.; Lioni, M.; Flaherty, K.T.; Herlyn, M. Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Mol. Cancer Ther., 2006, 5(5), 1136-1144.
88. Jiang, C.C.; Lai, F.; Thorne, R.F.; Yang, F.; Liu, H.; Hersey, P.; Zhang, X.D. MEK-independent survival of B-RAFV600E melanoma cells selected for resistance to apoptosis induced by the RAF inhibitor PLX4720. Clin. Cancer Res., 2010, Nov 18. [Epub ahead of print]
89. Smalley, K.S.; Lioni, M.; Dalla Palma, M.; Xiao, M.; Desai, B.; Egyhazi, S.; Hansson, J.; Wu, H.; King, A.J.; Van Belle, P.; Elder, D.E.; Flaherty, K.T.; Herlyn, M.; Nathanson, K.L. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol. Cancer Ther., 2008, 7(9), 2876-2883.
90. Paraiso, K.H.; Fedorenko, I.V.; Cantini, L.P.; Munko, A.C.; Hall, M.; Sondak, V.K.; Messina, J.L.; Flaherty, K.T.; Smalley, K.S. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Br. J. Cancer, 2010, 102(12), 1724-1730.
91. Villanueva, J.; Vultur, A.; Lee, J.T.; Somasundaram, R.; Fukunaga-Kalabis, M.; Cipolla, A.K.; Wubbenhorst, B.; Xu, X.; Gimotty, P.A.; Kee, D.; Santiago-Walker, A.E.; Letrero, R.; D'Andrea, K.; Pushparajan, A.; Hayden, J.E.; Brown, K.D.; Laquerre, S.; McArthur, G.A.; Sosman, J.A.; Nathanson, K.L.; Herlyn, M. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell, 2010, 18(6), 683-695.