Current Oncology Reports

, Volume 12, Issue 3, pp 146–152

B-RAF Inhibitors: An Evolving Role in the Therapy of Malignant Melanoma

  • Cynthia Shepherd
  • Igor Puzanov
  • Jeffrey A. Sosman


Immunotherapy and chemotherapy benefit few patients with metastatic melanoma, and even fewer experience durable survival benefit. These poor results come from treating melanoma as a single homogeneous disease. Recently, it has been shown that targeting activated tyrosine kinases (oncogenes) can mediate striking clinical benefits in several cancers. In 2002, a mutation at the V600E amino acid of the BRAF serine/threonine kinase was described as present in over 50% of melanomas. The mutation appeared to confer a dependency by the melanoma cancer cell on its activation of the MAP kinase pathway. The frequency and specificity of this mutation (95% at V600E of BRAF) suggests that it may be a potential target for therapy, and recent results with one inhibitor, PLX4032/RG7204, bare this out. This review updates the status of BRAF inhibitors in melanoma and what may be on the horizon.


Malignant melanoma B-RAF inhibitors 


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Jemal A, Siegel R, Ward E, et al.: Cancer statistics, 2009. CA Cancer J Clin 2009, 59:225–249.CrossRefPubMedGoogle Scholar
  2. 2.
    Chapman PB, Einhorn L H, Meyers ML, et al.: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 1999, 17:2745–2751.PubMedGoogle Scholar
  3. 3.
    Atkins MB, Lotze MT, Dutcher JP, et al.: High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999, 17:2105–2116.PubMedGoogle Scholar
  4. 4.
    Baselga J, Tripathy D, Mendelsohn J, et al.: Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer. Semin Oncol 1999, 26(Suppl 12):78–83.PubMedGoogle Scholar
  5. 5.
    Mauro MJ, O’Dwyer M, Heinrich MC, Druker BJ: STI571:a paradigm of new agents for cancer therapeutics. J Clin Oncol 2002, 20:325–334.CrossRefPubMedGoogle Scholar
  6. 6.
    •Kantarjian H, Sawyers C, Hochhaus A, et al.: Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002, 346:645–652. This is the first phase 2/3 experience with imatinib in CML, demonstrating remarkable responses (both hematologic and cytogenetic) in a large number of patients treated at tolerable doses.CrossRefPubMedGoogle Scholar
  7. 7.
    •Demetri GD, von Mehren M, Blanke CD, et al.: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002, 347:472–480. This is the initial phase 2 experience in gastrointestinal stromal tumors with imatinib, demonstrating a high response rate with some durable responses. It is the first example of targeted therapy efficacy in a solid tumor (sarcoma). The target was the presence of CKIT mutations.CrossRefPubMedGoogle Scholar
  8. 8.
    Heinrich MC, Corless CL, Demetri GD, et al.: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003, 21:4342–4349.CrossRefPubMedGoogle Scholar
  9. 9.
    •Lynch TJ, Bell DW, Sordella R, et al.: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004, 350:2129–2139. This is a description of activating tyrosine kinase mutations in the kinase domain of the EGFR that are associated with responsiveness to EGFR kinase inhibitor (gefitinib).CrossRefPubMedGoogle Scholar
  10. 10.
    Dancey JE: Epidermal growth factor receptor inhibitors in non-small cell lung cancer. Drugs 2007, 67:1125–1138.CrossRefPubMedGoogle Scholar
  11. 11.
    Karapetis CS, Khambata-Ford S, Jonker DJ, et al.: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Eng J Med 2008, 359:1757–1765.CrossRefGoogle Scholar
  12. 12.
    ••Weinstein IB, Joe A: Oncogene addiction. Cancer Res 2008, 68:3077–3080. This is a description of the concept of oncogene addiction, which is critical to targeted therapy and provides a rationale for the therapeutic window.CrossRefPubMedGoogle Scholar
  13. 13.
    ••Davies H, Bignell G, Cox C, et al.: Mutations in BRAF gene in human cancer. Nature 2002, 417:949–954. Sequencing of kinases in the MAP kinase pathway in a number of cancer cell lines reveals the presence of mutations in the BRAF gene in nearly 70% of melanoma samples (cell line, short-term cultures, or fresh tumor samples). These mutations are overwhelmingly found at the 599 amino acid (later determined to be 600) with a V to E mutation. The mutation appears to lead to transforming activity for the altered gene product.CrossRefPubMedGoogle Scholar
  14. 14.
    Satyamoorthy K, Li G, Gerrero MR, et al.: Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res 2003, 63:756–759.PubMedGoogle Scholar
  15. 15.
    Hingorani SR, Jacobetz MA, Robertson GP, et al.: Suppression of BRAF(V599E) in human melanoma abrogates transformation. Cancer Res 2003, 63:5198–5202.PubMedGoogle Scholar
  16. 16.
    Pollock PM, Harper UL, Hansen KS, et al.: High frequency of BRAF mutations in nevi. Nat Genet 2003, 33:19–20.CrossRefPubMedGoogle Scholar
  17. 17.
    Kumar R, Angelini S, Snellman E, Hemminki K: BRAF mutations are common somatic events in melanocytic nevi. J Invest Dermatol 2004, 122:342–348.CrossRefPubMedGoogle Scholar
  18. 18.
    Madhunapantula S, Robertson G: Is B-Raf a good therapeutic target for melanoma and other malignancies? Cancer Res 2008, 68:5–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Michaloglou C, Vredeveld LC, Soengas MS, et al.: BRAF V600E-associated senescence-like cell cycle arrest of human naevi. Nature 2005, 436:720–724.CrossRefPubMedGoogle Scholar
  20. 20.
    Huang PH, Marais R: Cancer: Melanoma troops massed. Nature 2009, 459:336–337.CrossRefPubMedGoogle Scholar
  21. 21.
    Garber K: Melanoma drug vindicates targeted approach. Science 2009, 326:1619.CrossRefPubMedGoogle Scholar
  22. 22.
    Viros A, Fridlyand J, Bauer J, et al.: Improving melanoma classification by integrating genetic and morphologic features. PLoS Med 2008, 5:e120.CrossRefPubMedGoogle Scholar
  23. 23.
    ••Curtin JA, Fridlyand J, Kageshita T, et al.: Distinct sets of genetic alterations in melanoma. N Engl J Med 2005, 353:2135–2147. This is the classic report of patients subset by type and site of melanoma and by genetic analysis of BRAF and NRAS mutations, as well as comparative genomic hybridization for copy numbers of other critical genes. A high degree of accuracy was obtained in assigning patients to four different subsets, which will have value in the development of new agents targeting these genetic alterations and clinicopathologic subsets. This study was also reviewed in Current Oncology Reports, volume 8, number 5.CrossRefPubMedGoogle Scholar
  24. 24.
    Beadling C, Jacobson-Dunlop E, Hodi FS, et al.: KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res 2008, 14:6821–6828.CrossRefPubMedGoogle Scholar
  25. 25.
    Curtin J, Busam K, Pinkel D, Bastian BC: Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006, 24:4340–4345.CrossRefPubMedGoogle Scholar
  26. 26.
    Albino AP, Nanus DM, Mentle IR, et al.: Analysis of ras oncogenes in malignant melanoma and precursor lesions: correlation of point mutations with differentiation phenotype. Oncogene 1989, 4:1363–1374.PubMedGoogle Scholar
  27. 27.
    •Van Raamsdonk CD, Bezrookove V, Green G, et al.: Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 2009, 457:599–602. In this description of activating point mutations in G-binding protein, GNAQ was found in over 40% of uveal melanomas as well as a high percentage of benign cutaneous blue nevi. Cells expressing this GNAQ mutation appear to be sensitive in vitro and in vivo to MEK inhibitors.CrossRefPubMedGoogle Scholar
  28. 28.
    Tsao H, Goel V, Wu H, et al.: Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol 2004, 122:337–341.CrossRefPubMedGoogle Scholar
  29. 29.
    Guldberg P, Thor Straten P, Birck A, et al.: Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res 1997, 57:3660–3663.PubMedGoogle Scholar
  30. 30.
    Sharpless N, Chin L: The INK4a/ARF locus and melanoma. Oncogene 2003, 22:3092–3098.CrossRefPubMedGoogle Scholar
  31. 31.
    Sosman JA, Margolin KA: Inside life of melanoma cell signaling, molecular insights, and therapeutic targets. Curr Oncol Rep 2009, 11:405–411.CrossRefPubMedGoogle Scholar
  32. 32.
    Sharma A,Trivedi NR, Zimmerman MA, et al: Mutant V599E B-RAF regulates growth and vascular development of malignant melanoma tumors. Cancer Res 2005, 65:2412–2421.CrossRefPubMedGoogle Scholar
  33. 33.
    Eisen T, Ahmad T, Flaherty KT, et al.: Sorafenib in advanced melanoma: a phase II randomized discontinuation trial analysis. Br J Cancer 2006, 95:581–586.CrossRefPubMedGoogle Scholar
  34. 34.
    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, 26:2178–2185.CrossRefPubMedGoogle Scholar
  35. 35.
    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, 27:2823–2830.CrossRefPubMedGoogle Scholar
  36. 36.
    Strumberg D: Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. Drugs Today 2005, 41:773–784.CrossRefPubMedGoogle Scholar
  37. 37.
    Smalley KS, Xiao M, Villanueva J, et al.: CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene 2009, 28:85–94.CrossRefPubMedGoogle Scholar
  38. 38.
    Tsai J, Lee JT, Wang W, et al.: Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent anti-melanoma activity. PNAS 2008, 105:3041–3046.CrossRefPubMedGoogle Scholar
  39. 39.
    Jalap B: Advances in the understanding and treatment of melanoma. Targeted therapeutics in melanoma: Changing the front end of drug development [abstract 011: 26.2006]. Presented at the Keystone Symposia.Google Scholar
  40. 40.
    King A, Patrick D, Bator sky R, et al.: Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res 2006, 66:11100–11105.CrossRefPubMedGoogle Scholar
  41. 41.
    Schwartz GK, Robertson S, Sheen A, et al.: A phase I study of XL281, a selective oral RAF kinase inhibitor, in patients (Pts) with advanced solid tumors [abstract]. J Clin Oncol 2009, 27(Suppl):3513.39.Google Scholar
  42. 42.
    Flaherty K, Puzanov I, Sosman J, et al.: Phase I study of PLX4032: proof of concept for V600E BRAF mutation as a therapeutic target in human cancer [abstract]. J Clin Oncol 2009, 27(Suppl):9000.Google Scholar
  43. 43.
    Flaherty Puzanov I, Kim KB, et al.: Selective inhibition of BRAF-V600E activating mutations induce major regressions in patients with metastatic melanoma. N Engl J Med 2010, submitted.Google Scholar
  44. 44.
    Engelmann JA, Settleman J: Acquired resistance to tyrosine kinase inhibitors during cancer therapy. Curr Opin Genet Dev 2008, 18:73–79.CrossRefGoogle Scholar
  45. 45.
    O’Hare T, Edie CA, Feininger MW: Crab kinase domain mutations, drug resistance, and the road to a cure for chromic myeloid leukemia. Blood 2007, 110:2242–2249.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Cynthia Shepherd
    • 1
  • Igor Puzanov
    • 1
  • Jeffrey A. Sosman
    • 1
  1. 1.Vanderbilt University Medical CenterNashvilleUSA

Personalised recommendations