Abstract
Selective inhibitors of the kinases BRAF and MEK for the treatment of patients with otherwise refractory BRAF mutant melanoma have demonstrated impressive efficacy, and combination treatment with these agents may prove to be even more effective. However, these drugs are not curative, mainly because of the relatively rapid development of drug resistance. Furthermore, they can produce undesired, and even unanticipated, side effects, including the emergence of neoplastic lesions harboring activating RAS mutations. Two recent reports reveal new considerations for the optimal approach to targeting this key oncogenic pathway in melanoma, highlighting the importance of combination treatment and therapeutic scheduling.
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Abbreviations
- CMML:
-
Chronic myelomonocytic leukemia
- EGFR:
-
Epidermal growth factor receptor
- SOX:
-
Sex determining region Y-box.
References
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, 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 BA, Cooper C, Shipley J, et al.: Mutations of the BRAF gene in human cancer. Nature. 2002, 417: 949-954. 10.1038/nature00766
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA, : Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011, 364: 2507-2516. 10.1056/NEJMoa1103782
Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D, : Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012, 367: 107-114. 10.1056/NEJMoa1203421
Corcoran RB, Settleman J, Engelman JA: Potential therapeutic strategies to overcome acquired resistance to BRAF or MEK inhibitors in BRAF mutant cancers. Oncotarget. 2011, 2: 336-346.
Gibney GT, Messina JL, Fedorenko IV, Sondak VK, Smalley KS: Paradoxical oncogenesis–the long-term effects of BRAF inhibition in melanoma. Nat Rev Clin Oncol. 2013, 10: 390-399. 10.1038/nrclinonc.2013.83
Sloot S, Fedorenko IV, Smalley KS, Gibney GT: Long-term effects of BRAF inhibitors in melanoma treatment: friend or foe?. Expert Opin Pharmacother. 2014, 15: 589-592. 10.1517/14656566.2014.881471
Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012, 367: 1694-1703. 10.1056/NEJMoa1210093
Abdel-Wahab O, Klimek VM, Gaskell A, Viale A, Cheng D, Kim E, Rampal R, Bluth M, Harding JJ, Callahan MK, Merghoob T, Berger MF, Solit DB, Rosen N, Levine RL, Chapman PB: Efficacy of intermittent combined RAF and MEK inhibition in a patient with concurrent BRAF and NRAS mutant malignancies. Cancer Discov. 2014
Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C, Haanen J, Blank C, Wesseling J, Willems SM, Zecchin D, Hobor S, Bajpe PK, Lieftink C, Mateus C, Vagner S, Grernrum W, Hofland I, Schlicker A, Wessels LF, Beijersbergen RL, Bardelli A, Di Nicolantonio F, Eggermont AM, Bernards R: Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature. 2014
Jain N, Curran E, Iyengar NM, Diaz-Flores E, Kunnavakkam R, Popplewell L, Kirschbaum MH, Karrison T, Erba HP, Green M, Poire X, Koval G, Shannon K, Reddy PL, Joseph L, Atallah EL, Dy P, Thomas SP, Smith SE, Doyle LA, Stadler WM, Larson RA, Stock W, Odenike O: Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res. 2014, 20: 490-498. 10.1158/1078-0432.CCR-13-1311
Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A, Bernards R: Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012, 483: 100-103. 10.1038/nature10868
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The author is an employee of Genentech, Inc. and a shareholder of Roche Pharmaceuticals.
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Settleman, J. Optimizing the treatment of BRAF mutant melanoma. Genome Med 6, 30 (2014). https://doi.org/10.1186/gm547
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DOI: https://doi.org/10.1186/gm547