Abstract
The activating BRAF mutation V600E and related mutations in this codon are most important for the activation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signalling pathway in melanoma. BRAF V600E mutations have been detected in ~40 % of melanoma patients and BRAF V600K mutations in ~5 % of melanoma patients. Activation of the MAPK pathway results in continuous stimulation of cell proliferation and inhibits programmed cell death. Vemurafenib (PLX4032) was developed as a low molecular weight molecule for the inhibition of the mutated serine threonine kinase BRAF, and it selectively binds to the ATP-binding site of BRAF-V600E kinase and inhibits its activity. The biochemical affinity of vemurafenib for mutated BRAF translates to potent inhibition of ERK phosphorylation and of cell proliferation exclusively in BRAF-mutant cell lines. In animal model experiments, it was demonstrated that vemurafenib achieved tumour regressions in cells harbouring the BRAF V600E mutation. The clinical trials with vemurafenib in unresectable metastatic melanoma in phase I, II, and III for patients harbouring BRAF V600E mutations demonstrated all unexpected high objective response rates ranging between 50 and 80 %. Median progression-free survival was prolonged from two months with dacarbazine to seven months with vemurafenib, and median overall survival was respectively prolonged from 9 to 14 months. A major problem that remains is the development of resistance to vemurafenib treatment after several months in the majority of patients, and multiple resistance mechanisms have already been described. Under vemurafenib treatment, about 25 % of patients developed cutaneous squamous cell carcinomas of the keratoacanthoma type with low invasive potential and without occurrence of metastasis. The overall tolerability of the drug was quite good, and a number of patients remained on treatment for long times. As other solid tumours like papillary thyroid cancer, colorectal cancer, non-small-cell lung cancer, and ovarian cancer likewise harbour BRAF mutation, vemurafenib is also tested in these entities. In future, combinations of vemurafenib with other kinase inhibitors and with immunotherapies will improve its therapeutic potential.
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References
Abusaif S, Jradi Z, Held L et al (2013) S100B and lactate dehydrogenase as response and progression markers during treatment with vemurafenib in patients with advanced melanoma. Melanoma Res 2013, Epub ahead of print
Balch CM, Gershenwald JE, Soong SJ et al (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27:6199–6206
Bollag G, Hirth P, Tsai J et al (2010) Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467:596–599
Carlson JA, Ross JS, Slominski A et al (2005) Molecular diagnostics in melanoma. J Am Acad Dermatol 52:743–775
Chapman PB, Hauschild A, Robert C et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516
Chapman PB, Hauschild A, Robert C et al (2012) Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. J Clin Oncol 30:8502
Davies H, Bignell GR, Cox C et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954
Dietrich S, Glimm H, Andrulis M, von Kalle C, Ho AD, Zenz T (2012) BRAF inhibition in refractory hairy-cell leukemia. N Engl J Med 366:2038–2040
Eigentler TK, Garbe C (2006) Malignant melanoma: classification and staging of malignant melanoma. Front Radiat Ther Oncol 39:149–158
European Medicines Agency (2013) Zelboraf—Annex I—Summary of product characteristics. 19 June 2013
Finck SJ, Giuliano AE, Morton DL (1983) LDH and melanoma. Cancer 51:840–843
Flaherty KT, Puzanov I, Kim KB et al (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363:809–819
Gautschi O, Pauli C, Strobel K et al (2012) A patient with BRAF V600E lung adenocarcinoma responding to vemurafenib. J Thorac Oncol 7:e23–e24
Gogas H, Eggermont AM, Hauschild A et al (2009) Biomarkers in melanoma. Ann Oncol 20(6):vi8–vi13
Greenman C, Stephens P, Smith R et al (2007) Patterns of somatic mutation in human cancer genomes. Nature 446:153–158
Hauschild A, Engel G, Brenner W et al (1999) S100B protein detection in serum is a significant prognostic factor in metastatic melanoma. Oncology 56:338–344
Hoffmann-La Roche Ltd (2012) Roche’s Zelboraf receives EU approval for the treatment of people with deadly form of skin cancer. http://www.roche.com/media/media_releases/med-cor-2012-02-20.htm
Kim KB, Cabanillas ME, Lazar AJ et al (2013) Clinical responses to vemurafenib in patients with metastatic papillary thyroid cancer harboring BRAF(V600E) mutation. Thyroid 23:1277–1283
Kopetz S, Desai J, Chan E et al (2010) PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumours. J Clin Oncol 28:3534
Mao M, Tian F, Mariadason JM et al (2013) Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin Cancer Res 19:657–667
Naoki K, Chen TH, Richards WG, Sugarbaker DJ, Meyerson M et al (2002) Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res 62:7001–7003
Oberholzer PA, Kee D, Dziunycz P et al (2012) RAS mutations are associated with the development of cutaneous squamous cell tumours in patients treated with RAF inhibitors. J Clin Oncol 30:316–321
Peyrade F, Re D, Ginet C et al (2013) Low-dose vemurafenib induces complete remission in a case of hairy-cell leukaemia with a V600E mutation. Haematologica 98:e20–e22
Peyssonnaux C, Eychene A (2001) The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell 93:53–62
Pflugfelder A, Eigentler TK, Keim U et al (2011) Effectiveness of carboplatin and paclitaxel as first- and second-line treatment in 61 patients with metastatic melanoma. PLoS One 6:e16882
Prahallad A, Sun C, Huang S et al (2012) Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483:100–103
Schreck R, Rapp UR (2006) Raf kinases: oncogenesis and drug discovery. Int J Cancer 119:2261–2271
Shah N, Iyer RM, Mair HJ et al (2013) Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process. J Pharm Sci 102:967–981
Sirott MN, Bajorin DF, Wong GY et al (1993) Prognostic factors in patients with metastatic malignant melanoma: a multivariate analysis. Cancer 72:3091–3098
Sosman JA, Kim KB, Schuchter L et al (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366:707–714
Tanaka H, Deng G, Matsuzaki K et al (2006) BRAF mutation, CpG island methylator phenotype and microsatellite instability occur more frequently and concordantly in mucinous than non-mucinous colorectal cancer. Int J Cancer 118:2765–2771
Tiacci E, Trifonov V, Schiavoni G et al (2011) BRAF mutations in hairy-cell leukemia. N Engl J Med 364:2305–2315
Tie J, Gibbs P, Lipton L et al (2011) Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAF(V600E) mutation. Int J Cancer 128:2075–2084
U.S. Food and Drug Administration (2011) FDA approves Zelboraf and companion diagnostic test for late-stage skin cancer. http://www.roche.com/media/media_releases/med-cor-2012-02-20.htm
Weide B, Elsasser M, Buttner P et al (2012) Serum markers lactate dehydrogenase and S100B predict independently disease outcome in melanoma patients with distant metastasis. Br J Cancer 107:422–428
Xing M (2007) BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr Rev 28:742–762
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Garbe, C., Abusaif, S., Eigentler, T.K. (2014). Vemurafenib. In: Martens, U. (eds) Small Molecules in Oncology. Recent Results in Cancer Research, vol 201. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-54490-3_13
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DOI: https://doi.org/10.1007/978-3-642-54490-3_13
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