Abstract
The hunt for mutated and activated kinases in cancer has proceeded at an accelerated pace since the successful treatment of chronic myelogenous leukemia with imatinib and with the development of new genomic sequencing technologies. The identification of activating mutations in B-Raf in a major subset of melanomas was first reported in 2002. Basic laboratory experiments confirmed the ability of mutant B-Raf to function as a driver oncogene in vivo. Relatively rapidly, inhibitors that preferentially target the mutated kinase were developed and tested clinically, and these studies revealed that the majority of patients bearing V600E B-Raf mutant melanomas showed a clinical response. Positive results of a randomized phase III clinical trial were released in early 2011. The current phase of this remarkable story is focused upon understanding mechanisms of primary and secondary resistance to B-Raf inhibitors in the clinic.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Wu J, Rosenbaum E, Begum S, Westra WH. Distribution of BRAF T1799A(V600E) mutations across various types of benign nevi: implications for melanocytic tumorigenesis. Am J Dermatopathol. 2007;29(6):534–7.
Poynter JN, Elder JT, Fullen DR, et al. BRAF and NRAS mutations in melanoma and melanocytic nevi. Melanoma Res. 2006;16(4):267–73.
Dankort D, Curley DP, Cartlidge RA, et al. BrafV600E cooperates with Pten loss to induce metastatic melanoma. Nat Genet. 2009;41(5):544–52.
Weber CK, Slupsky JR, Kalmes HA, Rapp UR. Active Ras induces heterodimerization of cRaf and BRaf. Cancer Res. 2001;61(9):3595–8.
Rajakulendran T, Sahmi M, Lefrancois M, Sicheri F, Therrien M. A dimerization-dependent mechanism drives RAF catalytic activation. Nature. 2009;461(7263):542–5.
Rushworth LK, Hindley AD, O’Neill E, Kolch W. Regulation and role of Raf-1/B-Raf heterodimerization. Mol Cell Biol. 2006;26(6):2262–72.
Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464(7287):431–5.
Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464(7287):427–30.
Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors. 2006;24(1):21–44.
Pratilas, Solit. Clin Cancer Res. 2010 (in press).
Dougherty MK, Muller J, Ritt DA, et al. Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell. 2005;17(2):215–24.
Tsavachidou D, Coleman ML, Athanasiadis G, et al. SPRY2 is an inhibitor of the ras/extracellular signal-regulated kinase pathway in melanocytes and melanoma cells with wild-type BRAF but not with the V599E mutant. Cancer Res. 2004;64(16):5556–9.
Kim HJ, Bar-Sagi D. Modulation of signalling by Sprouty: a developing story. Nat Rev Mol Cell Biol. 2004;5(6):441–50.
Keyse SM. Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev. 2008;27(2):253–61.
Brady SC, Coleman ML, Munro J, Feller SM, Morrice NA, Olson MF. Sprouty2 association with B-Raf is regulated by phosphorylation and kinase conformation. Cancer Res. 2009;69(17):6773–81.
Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.
Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135–47.
Cohen Y, Rosenbaum E, Begum S, et al. Exon 15 BRAF mutations are uncommon in melanomas arising in nonsun-exposed sites. Clin Cancer Res. 2004;10(10):3444–7.
Edwards RH, Ward MR, Wu H, et al. Absence of BRAF mutations in UV-protected mucosal melanomas. J Med Genet. 2004;41(4):270–2.
Edmunds SC, Cree IA, Di Nicolantonio F, Hungerford JL, Hurren JS, Kelsell DP. Absence of BRAF gene mutations in uveal melanomas in contrast to cutaneous melanomas. Br J Cancer. 2003;88(9):1403–5.
Kumar R, Angelini S, Czene K, et al. BRAF mutations in metastatic melanoma: a possible association with clinical outcome. Clin Cancer Res. 2003;9(9):3362–8.
Houben R, Becker JC, Kappel A, et al. Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. J Carcinog. 2004;3(1):6.
Chang D, Panageas K, Osman I, Polsky D, Busam K, Chapman P. Clinical significance of BRAF mutations in metastatic melanoma. J Transl Med. 2004;2(1):46.
Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140(2):209–21.
Pratilas CA, Taylor BS, Ye Q, et al. (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci USA. 2009;106(11):4519–24.
Hingorani SR, Jacobetz MA, Robertson GP, Herlyn M, Tuveson DA. Suppression of BRAF(V599E) in human melanoma abrogates transformation. Cancer Res. 2003;63(17):5198–202.
Karasarides M, Chiloeches A, Hayward R, et al. B-RAF is a therapeutic target in melanoma. Oncogene. 2004;23(37):6292–8.
Tsai J, Lee JT, Wang W, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci USA. 2008;105(8):3041–6.
Heidorn SJM C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, Hussain J, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140(2):209–21.
Puzanov I, Nathason KL, Chapman PB, Xu X, Sosman JA, McArthur GA, Ribas A, Kim KB, Grippo JF, Flaherty KT. PLX4032, a highly selective V600EBRAF kinase inhibitor: clinical correlation of activity with pharmacokinetic and pharmacodynamic parameters in a phase I trial. J Clin Oncol. 2009;27(15s).
Eisen T, Ahmad T, Flaherty KT, et al. Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer. 2006;95(5):581–6.
Hauschild A, Agarwala SS, Trefzer U, et al. 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):2823–30.
McDermott DF, Sosman JA, Gonzalez R, et al. Double-blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: a report from the 11715 Study Group. J Clin Oncol. 2008;26(13):2178–85.
Kefford R, Arkenau H, Brown MP, Millward M, Infante JR, Long GV, Ouellet D, Curtis M, Lebowitz PF, Falchook GS. Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors. J Clin Oncol. 2010;28(7s).
Dummer RR C, Chapman PB, Sosman JA, Middleton M, Bastholt L, Kemsley K, et al. AZD6244 (ARRY-142886) vs temozolomide (TMZ) in patients (pts) with advanced melanoma: an open-label, randomized, multicenter, phase II study. J Clin Oncol. 2008;26(May 20 suppl):9033.
Infante JR, Fecher LA, Nallapareddy S, Gordon MS, Flaherty KT, Cox DS, DeMarini DJ, Morris SR, Burris HA, Messersmith WA. Safety and efficacy results from the first-in-human study of the oral MEK 1/2 inhibitor GSK1120212. J Clin Oncol. 2010;28(7s).
Solit DB, Garraway LA, Pratilas CA, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439(7074):358–62.
Adjei AA, Cohen RB, Franklin W, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008;26(13):2139–46.
Montagut C, Sharma SV, Shioda T, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68(12):4853–61.
Nazarian et al. Nature 2010.
Villanueva J et al. Cancer Cell 2010.
Dumaz N, Hayward R, Martin J, et al. In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res. 2006;66(19):9483–91.
Johannesen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition throught MAP Kinase pathway reactivation. Nature 2010;468:968–72.
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med.2010; 363:711–23.
Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-Cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70(13):5213–9.
O’Day SJ, Kim KB, Sosman JA, et al. 23LBA BEAM: A randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated Advanced Melanoma. 2009;7:13.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Chapman, P.B., Flaherty, K. (2012). Targeted Inhibition of B-Raf. In: Gajewski, T., Hodi, F. (eds) Targeted Therapeutics in Melanoma. Current Clinical Oncology. Springer, New York, NY. https://doi.org/10.1007/978-1-61779-407-0_5
Download citation
DOI: https://doi.org/10.1007/978-1-61779-407-0_5
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-61779-406-3
Online ISBN: 978-1-61779-407-0
eBook Packages: MedicineMedicine (R0)