Abstract
Melanoma is characterized by frequent mutations in the serine-threonine kinase encoding gene BRAF, triggering unrestrained MAPK signaling. In the 40–50% of patients harboring these mutations, inhibiting mutant BRAF or its downstream signaling partner MEK leads to dramatic clinical benefits in patients. Although either BRAF or MEK inhibitors improve outcomes compared with cytotoxic chemotherapy, acquired resistance occurs within 9–12 months in almost all patients and is largely due to MAPK signaling reactivation. Combined BRAF and MEK inhibition forestalls this resistance and has led to improved survival in patients with metastatic BRAF-mutant melanoma with a median progression-free survival of approximately 1 year. Acquired resistance remains a major barrier to long-term success although up to 20% of patients have durable responses (lasting >5 years) with these agents. Combining these MAPK pathway inhibitors with immunotherapies and achieving more thorough pathway blockade (e.g., with ERK inhibitors) are ongoing areas of research.
This is a preview of subscription content, log in via an institution.
References
Abdel-Wahab O, Klimek VM, Gaskell AA, Viale A, Cheng D, Kim E, Rampal R, Bluth M, Harding JJ, Callahan MK et al (2014) Efficacy of intermittent combined RAF and MEK inhibition in a patient with concurrent BRAF- and NRAS-mutant malignancies. Cancer Discov 4:538–545
Abel EV, Basile KJ, Kugel CH III, Witkiewicz AK, Le K, Amaravadi RK, Karakousis GC, Xu X, Xu W, Schuchter LM et al (2013) Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3. J Clin Investig 123: 2155–2168
Ascierto PA, Mcarthur GA, Dreno B, Atkinson V, Liszkay G, Di Giacomo AM, Mandala M, Demidov L, Stroyakovskiy D, Thomas L et al (2016) Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 17:1248–1260
Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G et al (2010) Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467: 596–599
Boshuizen J, Koopman LA, Krijgsman O, Shahrabi A, Van Den Heuvel EG, Ligtenberg MA, Vredevoogd DW, Kemper K, Kuilman T, Song JY et al (2018) Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors. Nat Med 24:203–212
Callahan MK, Rampal R, Harding JJ, Klimek VM, Chung YR, Merghoub T, Wolchok JD, Solit DB, Rosen N, Abdel-Wahab O et al (2012) Progression of RAS-mutant leukemia during RAF inhibitor treatment. N Engl J Med 367:2316–2321
Capparelli C, Rosenbaum S, Berger AC, Aplin AE (2015) Fibroblast-derived neuregulin 1 promotes compensatory ErbB3 receptor signaling in mutant BRAF melanoma. J Biol Chem 290:24267–24277
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516
Chen G, Mcquade JL, Panka DJ, Hudgens CW, Amin-Mansour A, Mu XJ, Bahl S, Jane-Valbuena J, Wani KM, Reuben A et al (2016) Clinical, molecular, and immune analysis of dabrafenib–trametinib combination treatment for BRAF inhibitor-refractory metastatic melanoma: a phase 2 clinical trial. JAMA Oncol 2:1056–1064
Dahlman KB, Xia J, Hutchinson K, Ng C, Hucks D, Jia P, Atefi M, Su Z, Branch S, Lyle P et al (2012) BRAF L597 mutations in melanoma are associated with sensitivity to MEK inhibitors. Cancer Discov 2:791–797
Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, Dummer R, Mcmahon M, Stuart DD (2013) Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494:251–255
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954
Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R et al (2018) Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 19:603–615
Ebert PJ, Cheung J, Yang Y, Mcnamara E, Hong R, Moskalenko M, Gould SE, Maecker H, Irving BA, Kim JM et al (2016) MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 44:609–621
Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, Kim JJ, Hatton C, Chopra R, Oberholzer PA, Karpova MB et al (2009) MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A 106:20411–20416
Eroglu Z, Chen YA, Gibney GT, Weber JS, Kudchadkar RR, Khushalani NI, Markowitz J, Brohl AS, Tetteh LF, Ramadan H et al (2018) Combined BRAF and HSP90 inhibition in patients with unresectable BRAF V600E mutant melanoma. Clin Cancer Res 24:5516–5524
Falchook GS, Lewis KD, Infante JR, Gordon MS, Vogelzang NJ, Demarini DJ, Sun P, Moy C, Szabo SA, Roadcap LT et al (2012a) Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 13:782–789
Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, Hamid O, Infante JR, Millward M, Pavlick AC et al (2012b) Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 379:1893–1901
Fallahi-Sichani M, Moerke NJ, Niepel M, Zhang T, Gray NS, Sorger PK (2015) Systematic analysis of BRAF(V600E) melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis. Mol Syst Biol 11:797
Fedorenko IV, Wargo JA, Flaherty KT, Messina JL, Smalley KS (2015) BRAF inhibition generates a host-tumor niche that mediates therapeutic escape. J Invest Dermatol 135:3115–3124
Fedorenko IV, Abel EV, Koomen JM, Fang B, Wood ER, Chen YA, Fisher KJ, Iyengar S, Dahlman KB, Wargo JA et al (2016) Fibronectin induction abrogates the BRAF inhibitor response of BRAF V600E/PTEN-null melanoma cells. Oncogene 35:1225–1235
Flaherty KT, Puzanov I, Kim KB, Ribas A, Mcarthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K et al (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363:809–819
Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N et al (2012a) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367:1694–1703
Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P et al (2012b) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367:107–114
Flaherty KT, Lee SJ, Zhao F, Schuchter LM, Flaherty L, Kefford R, Atkins MB, Leming P, Kirkwood JM (2013) Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol 31:373–379
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6:pl1
Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, Beroukhim R, Milner DA, Granter SR, Du J et al (2005) Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436:117–122
Ge X, Fu YM, Meadows GG (2002) U0126, a mitogen-activated protein kinase kinase inhibitor, inhibits the invasion of human A375 melanoma cells. Cancer Lett 179:133–140
Girotti MR, Pedersen M, Sanchez-Laorden B, Viros A, Turajlic S, Niculescu-Duvaz D, Zambon A, Sinclair J, Hayes A, Gore M et al (2013) Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. Cancer Discov 3:158–167
Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E et al (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380:358–365
Hugo W, Shi H, Sun L, Piva M, Song C, Kong X, Moriceau G, Hong A, Dahlman KB, Johnson DB et al (2015) Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 162: 1271–1285
Hu-Lieskovan S, Mok S, Homet Moreno B, Tsoi J, Robert L, Goedert L, Pinheiro EM, Koya RC, Graeber TG, Comin-Anduix B et al (2015) Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma. Sci Transl Med 7:279ra41
Hutchinson KE, Lipson D, Stephens PJ, Otto G, Lehmann BD, Lyle PL, Vnencak-Jones CL, Ross JS, Pietenpol JA, Sosman JA et al (2013) BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition. Clin Cancer Res 19:6696–6702
Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A et al (2015) Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 373:726–736
Jameson KL, Mazur PK, Zehnder AM, Zhang J, Zarnegar B, Sage J, Khavari PA (2013) IQGAP1 scaffold-kinase interaction blockade selectively targets RAS–MAP kinase-driven tumors. Nat Med 19: 626–630
Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, Barretina J et al (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468:968–972
Johannessen CM, Johnson LA, Piccioni F, Townes A, Frederick DT, Donahue MK, Narayan R, Flaherty KT, Wargo JA, Root DE et al (2013) A melanocyte lineage program confers resistance to MAP kinase pathway inhibition. Nature 504:138–142
Johnson DB, Flaherty KT, Weber JS, Infante JR, Kim KB, Kefford RF, Hamid O, Schuchter L, Cebon J, Sharfman WH et al (2014a) Combined BRAF (dabrafenib) and MEK inhibition (trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. J Clin Oncol 32:3697–3704
Johnson DB, Smalley KS, Sosman JA (2014b) Molecular pathways: targeting NRAS in melanoma and acute myelogenous leukemia. Clin Cancer Res 20: 4186–4192
Johnson DB, Menzies AM, Zimmer L, Eroglu Z, Ye F et al (2015) BRAF inhibitor acquired resistance: a multicenter meta-analysis of the spectrum and clinical implications of resistance mechanisms. J Clin Oncol 33:Abstr 9008
Johnson DB, Roszik J, Shoushtari AN, Eroglu Z, Balko J, Higham C, Puzanov I, Patel SP, Sosman JA, Woodman SE (2016) Comparative analysis of the GNAQ, GNA11, SF3B1, and EIF1AX driver mutations in melanoma and across the cancer spectrum. Pigment Cell Melanoma Res 29:470–473
Kirkwood JM, Bastholt L, Robert C, Sosman J, Larkin J, Hersey P, Middleton M, Cantarini M, Zazulina V, Kemsley K et al (2012) Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res 18:555–567
Koelblinger P, Dornbierer J, Dummer R (2017) A review of binimetinib for the treatment of mutant cutaneous melanoma. Future Oncol 13:1755–1766
Koelblinger P, Thuerigen O, Dummer R (2018) Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol 30:125–133
Konieczkowski DJ, Johannessen CM, Abudayyeh O, Kim JW, Cooper ZA, Piris A, Frederick DT, Barzily-Rokni M, Straussman R, Haq R et al (2014) A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Discov 4:816–827
Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, Mandala M, Demidov L, Stroyakovskiy D, Thomas L et al (2014) Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371:1867–1876
Lito P, Pratilas CA, Joseph EW, Tadi M, Halilovic E, Zubrowski M, Huang A, Wong WL, Callahan MK, Merghoub T et al (2012) Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 22:668–682
Loi S, Dushyanthen S, Beavis PA, Salgado R, Denkert C, Savas P, Combs S, Rimm DL, Giltnane JM, Estrada MV et al (2015) RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. Clin Cancer Res 22:1499–1509
Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A et al (2012) Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 13:1087–1095
Long GV, Stroyakovskiy D, Gogas H, Levchenko E, De Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ et al (2014) Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 371:1877–1888
Long GV, Stroyakovskiy D, Gogas H, Levchenko E, De Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ et al (2015) Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386: 444–451
Long GV, Weber JS, Infante JR, Kim KB, Daud A, Gonzalez R, Sosman JA, Hamid O, Schuchter L, Cebon J et al (2016) Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib. J Clin Oncol 34:871–878
Lorusso P, Krishnamurthi S, Rinehart JR, Nabell L, Croghan G, Varterasian M, Sadis SS, Menon SS, Leopold J, Meyer MB (2005) A phase 1–2 clinical study of a second generation oral MEK inhibitor, PD 0325901 in patients with advanced cancer. J Clin Oncol 23:3011
Minor DR, Puzanov I, Callahan MK, Hug BA, Hoos A (2015) Severe gastrointestinal toxicity with administration of trametinib in combination with dabrafenib and ipilimumab. Pigment Cell Melanoma Res 28:611–612
Moriceau G, Hugo W, Hong A, Shi H, Kong X, Yu CC, Koya RC, Samatar AA, Khanlou N, Braun J et al (2015) Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction. Cancer Cell 27:240–256
Morris EJ, Jha S, Restaino CR, Dayananth P, Zhu H, Cooper A, Carr D, Deng Y, Jin W, Black S et al (2013) Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov 3:742–750
Moschos SJ, Sullivan RJ, Hwu WJ, Ramanathan RK, Adjei AA, Fong PC, Shapira-Frommer R, Tawbi HA, Rubino J, Rush TS III et al (2018) Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors. JCI Insight 3:pii: 92352
Muller J, Krijgsman O, Tsoi J, Robert L, Hugo W, Song C, Kong X, Possik PA, Cornelissen-Steijger PD, Foppen MH et al (2014) Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat Commun 5:5712
Nathanson KL, Martin AM, Wubbenhorst B, Greshock J, Letrero R, D’Andrea K, O’Day S, Infante JR, Falchook GS, Arkenau HT et al (2013) Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436). Clin Cancer Res 19:4868–4878
Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H et al (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973–977
Okimoto RA, Lin L, Olivas V, Chan E, Markegard E, Rymar A, Neel D, Chen X, Hemmati G, Bollag G et al (2016) Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF-mutant lung cancer. Proc Natl Acad Sci U S A 113:13456–13461
Paraiso KH, Fedorenko IV, Cantini LP, Munko AC, Hall M, Sondak VK, Messina JL, Flaherty KT, Smalley KS (2010) Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Br J Cancer 102:1724–1730
Patel SP, Lazar AJ, Papadopoulos NE, Liu P, Infante JR, Glass MR, Vaughn CS, Lorusso PM, Cohen RB, Davies MA et al (2013) Clinical responses to selumetinib (AZD6244; ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma. Cancer 119:799–805
Ramirez M, Rajaram S, Steininger RJ, Osipchuk D, Roth MA, Morinishi LS, Evans L, Ji W, Hsu CH, Thurley K et al (2016) Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells. Nat Commun 7:10690
Ramsdale R, Jorissen RN, Li FZ, Al-Obaidi S, Ward T, Sheppard KE, Bukczynska PE, Young RJ, Boyle SE, Shackleton M et al (2015) The transcription cofactor c-JUN mediates phenotype switching and BRAF inhibitor resistance in melanoma. Sci Signal 8:ra82
Ravindran Menon D, Das S, Krepler C, Vultur A, Rinner B, Schauer S, Kashofer K, Wagner K, Zhang G, Bonyadi Rad E et al (2015) A stress-induced early innate response causes multidrug tolerance in melanoma. Oncogene 34:4448–4459
Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J (2013) Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 368:1365–1366
Ribas A, Gonzalez R, Pavlick A, Hamid O, Gajewski TF, Daud A, Flaherty L, Logan T, Chmielowski B, Lewis K et al (2014) Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol 15:954–965
Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L et al (2014) Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372:30–39
Rosen LS, Lorusso P, Ma WW, Goldman JW, Weise A, Colevas AD, Adjei A, Yazji S, Shen A, Johnston S et al (2016) A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. Investig New Drugs 34:604–613
Samatar AA, Poulikakos PI (2014) Targeting RAS–ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov 13:928–942
Satyamoorthy K, Li G, Vaidya B, Patel D, Herlyn M (2001) Insulin-like growth factor-1 induces survival and growth of biologically early melanoma cells through both the mitogen-activated protein kinase and beta-catenin pathways. Cancer Res 61:7318–7324
Schreuer M, Jansen Y, Planken S, Chevolet I, Seremet T, Kruse V, Neyns B (2017) Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAFV600-mutant melanoma: an open-label, single arm, dual-centre, phase 2 clinical trial. Lancet Oncol 18:464–472
Sharma R, Fedorenko I, Spence PT, Sondak VK, Smalley KS, Koomen JM (2016) Activity-based protein profiling shows heterogeneous signaling adaptations to BRAF inhibition. J Proteome Res 15: 4476–4489
Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, Chodon T, Guo R, Johnson DB, Dahlman KB et al (2014) Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov 4:80–93
Smalley KS, Lioni M, Palma MD, Xiao M, Desai B, Egyhazi S, Hansson J, Wu H, King AJ, Van Belle P et al (2008) Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther 7:2876–2883
Smith MP, Brunton H, Rowling EJ, Ferguson J, Arozarena I, Miskolczi Z, Lee JL, Girotti MR, Marais R, Levesque MP et al (2016) Inhibiting drivers of non-mutational drug tolerance is a salvage strategy for targeted melanoma therapy. Cancer Cell 29: 270–284
Smyth T, Paraiso KH, Hearn K, Rodriguez-Lopez AM, Munck JM, Haarberg HE, Sondak VK, Thompson NT, Azab M, Lyons JF et al (2014) Inhibition of HSP90 by AT13387 delays the emergence of resistance to BRAF inhibitors and overcomes resistance to dual BRAF and MEK inhibition in melanoma models. Mol Cancer Ther 13:2793–2804
Somasundaram R, Zhang G, Fukunaga-Kalabis M, Perego M, Krepler C, Xu X, Wagner C, Hristova D, Zhang J, Tian T et al (2017) Tumor-associated B-cells induce tumor heterogeneity and therapy resistance. Nat Commun 8:607
Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, Mcarthur GA, Hutson TE, Moschos SJ, Flaherty KT et al (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366:707–714
Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du JY, Davis A, Mongare MM, Gould J, Frederick DT et al (2012) Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487:500–504
Su Y, Vilgelm AE, Kelley MC, Hawkins OE, Liu Y, Boyd KL, Kantrow S, Splittgerber RC, Short SP, Sobolik T et al (2012) RAF265 inhibits the growth of advanced human melanoma tumors. Clin Cancer Res 18:2184–2198
Sullivan RJ, Gonzalez R, Lewis KD, Hamid O, Infante JR, Patel MR, Hodi FS, Wallin J, Pitcher B, Cha E et al (2017) Atezolizumab (A) + cobimetinib (C) + vemurafenib (V) in BRAFV600-mutant metastatic melanoma (mel): updated safety and clinical activity. J Clin Oncol 35:3063–3063
Sullivan RJ, Infante JR, Janku F, Wong DJL, Sosman JA, Keedy V, Patel MR, Shapiro GI, Mier JW, Tolcher AW et al (2018) First-in-class ERK1/2 inhibitor ulixertinib (BVD-523) in patients with MAPK mutant advanced solid tumors: results of a phase I dose-escalation and expansion study. Cancer Discov 8:184–195
Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C, Haanen J, Blank C, Wesseling J, Willems SM et al (2014) Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 508: 118–122
Tiacci E, Park JH, De Carolis L, Chung SS, Broccoli A, Scott S, Zaja F, Devlin S, Pulsoni A, Chung YR et al (2015) Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med 373:1733–1747
Titz B, Lomova A, Le A, Hugo W, Kong X, Ten Hoeve J, Friedman M, Shi H, Moriceau G, Song C et al (2016) JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma. Cell Discov 2:16028
Tsao H, Zhang X, Fowlkes K, Haluska FG (2000) Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines. Cancer Res 60: 1800–1804
Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O’Brien JM, Simpson EM, Barsh GS, Bastian BC (2009) Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457:599–602
Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, Wubbenhorst B, Xu X, Gimotty PA, Kee D et al (2010) 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 18:683–695
Villanueva J, Infante JR, Krepler C, Reyes-Uribe P, Samanta M, Che H-Y, Swoboda R, Wilson M, Vultur A, Fukunaga-Kalabis M et al (2013) Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep 4:1090–1099
Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, Kehoe SM, Johannessen CM, Macconaill LE, Hahn WC et al (2011) Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol 29:3085–3096
Wagle N, Van Allen EM, Treacy DJ, Frederick DT, Cooper ZA, Taylor-Weiner A, Rosenberg M, Goetz EM, Sullivan RJ, Farlow DN et al (2014) MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov 4:61–68
Watson IR, Li L, Cabeceiras PK, Mahdavi M, Gutschner T, Genovese G, Wang G, Fang Z, Tepper JM, Stemke-Hale K et al (2014) The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF. Cancer Res 74:4845–4852
Webster MR, Xu M, Kinzler KA, Kaur A, Appleton J, O’Connell MP, Marchbank K, Valiga A, Dang VM, Perego M et al (2015) Wnt5A promotes an adaptive, senescent-like stress response, while continuing to drive invasion in melanoma cells. Pigment Cell Melanoma Res 28:184–195
Wellbrock C, Arozarena I (2015) Microphthalmia-associated transcription factor in melanoma development and MAP-kinase pathway targeted therapy. Pigment Cell Melanoma Res 28:390–406
Whittaker S, Kirk R, Hayward R, Zambon A, Viros A, Cantarino N, Affolter A, Nourry A, Niculescu-Duvaz D, Springer C et al (2010) Gatekeeper mutations mediate resistance to BRAF-targeted therapies. Sci Transl Med 2:35ra41
Woods D, Cherwinski H, Venetsanakos E, Bhat A, Gysin S, Humbert M, Bray PF, Saylor VL, Mcmahon M (2001) Induction of beta3-integrin gene expression by sustained activation of the Ras-regulated Raf–MEK–extracellular signal-regulated kinase signaling pathway. Mol Cell Biol 21:3192–3205
Xing F, Persaud Y, Pratilas CA, Taylor BS, Janakiraman M, She QB, Gallardo H, Liu C, Merghoub T, Hefter B et al (2012) Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF. Oncogene 31:446–457
Xue Y, Martelotto L, Baslan T, Vides A, Solomon M, Mai TT, Chaudhary N, Riely GJ, Li BT, Scott K et al (2017) An approach to suppress the evolution of resistance in BRAF(V600E)-mutant cancer. Nat Med 23:929–937
Zhang XD, Borrow JM, Zhang XY, Nguyen T, Hersey P (2003) Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria. Oncogene 22: 2869–2881
Zhang C, Spevak W, Zhang Y, Burton EA, Ma Y, Habets G, Zhang J, Lin J, Ewing T, Matusow B et al (2015) RAF inhibitors that evade paradoxical MAPK pathway activation. Nature 526:583–586
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this entry
Cite this entry
Johnson, D.B., Dummer, R., Flaherty, K.T., Smalley, K.S. (2019). Targeted Therapies for BRAF-Mutant Metastatic Melanoma. In: Balch, C., et al. Cutaneous Melanoma. Springer, Cham. https://doi.org/10.1007/978-3-319-46029-1_40-1
Download citation
DOI: https://doi.org/10.1007/978-3-319-46029-1_40-1
Received:
Accepted:
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-46029-1
Online ISBN: 978-3-319-46029-1
eBook Packages: Springer Reference MedicineReference Module Medicine