173
Views
0
CrossRef citations to date
0
Altmetric
Review

NRAS Mutant Melanoma: An Overview for the Clinician for Melanoma Management

&
Pages 47-59 | Accepted 06 Nov 2015, Published online: 17 Feb 2016

References

  • Lo JA , FisherDE . The melanoma revolution: from UV carcinogenesis to a new era in therapeutics . Science346 ( 6212 ), 945 – 949 ( 2014 ).
  • Sullivan R , LorussoP, BoernerS, DummerR . Achievements and challenges of molecular targeted therapy in melanoma . Am. Soc. Clin. Oncol. Educ. Book35, 177 – 186 ( 2015 ).
  • Eggermont AM , MaioM, RobertC . Immune checkpoint inhibitors in melanoma provide the cornerstones for curative therapies . Semin. Oncol.42 ( 3 ), 429 – 435 ( 2015 ).
  • Davies H , BignellGR, CoxCet al. Mutations of the BRAF gene in human cancer . Nature417 ( 6892 ), 949 – 954 ( 2002 ).
  • Wan PT , GarnettMJ, RoeSMet al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF . Cell116 ( 6 ), 855 – 867 ( 2004 ).
  • Flaherty KT , PuzanovI, KimKBet al. Inhibition of mutated, activated braf in metastatic melanoma . N. Engl. J. Med.363 ( 9 ), 809 – 819 ( 2010 ).
  • Chapman PB , HauschildA, RobertCet al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation . N. Engl. J. Med.364 ( 26 ), 2507 – 2516 ( 2011 ).
  • Flaherty KT , InfanteJR, DaudAet al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations . N. Engl. J. Med.367 ( 18 ), 1694 – 1703 ( 2012 ).
  • Long GV , StroyakovskiyD, GogasHet al. Combined BRAF and mek inhibition versus BRAF inhibition alone in melanoma . N. Engl. J. Med.371 ( 20 ), 1877 – 1888 ( 2014 ).
  • Robert C , KaraszewskaB, SchachterJet al. Improved overall survival in melanoma with combined dabrafenib and trametinib . N. Engl. J. Med.372 ( 1 ), 30 – 39 ( 2015 ).
  • Hodi FS , O'daySJ, McdermottDFet al. Improved survival with ipilimumab in patients with metastatic melanoma . N. Engl. J. Med.363 ( 8 ), 711 – 723 ( 2010 ).
  • Schadendorf D , HodiFS, RobertCet al. Pooled analysis of long-term survival data from Phase II and Phase III trials of ipilimumab in unresectable or metastatic melanoma . J. Clin. Oncol.33 ( 17 ), 1889 – 1894 ( 2015 ).
  • Larkin J , Chiarion-SileniV, GonzalezRet al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma . N. Engl. J. Med.373 ( 1 ), 23 – 34 ( 2015 ).
  • Robert C , SchachterJ, LongGVet al. Pembrolizumab versus ipilimumab in advanced melanoma . N. Engl. J. Med.372 ( 26 ), 2521 – 2532 ( 2015 ).
  • Postow MA , ChesneyJ, PavlickACet al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma . N. Engl. J. Med.372 ( 21 ), 2006 – 2017 ( 2015 ).
  • Posch C , Ortiz-UrdaS . Nras mutant melanoma – undrugable?Oncotarget4 ( 4 ), 494 – 495 ( 2013 ).
  • Malumbres M , BarbacidM . Ras oncogenes: The first 30 years . Nat. Rev. Cancer3 ( 6 ), 459 – 465 ( 2003 ).
  • Karnoub AE , WeinbergRA . Ras oncogenes: split personalities . Nat. Rev. Mol. Cell Biol.9 ( 7 ), 517 – 531 ( 2008 ).
  • Forbes SA , BindalN, BamfordSet al. Cosmic: mining complete cancer genomes in the catalogue of somatic mutations in cancer . Nucleic Acids Res.39 ( Database issue ), D945 – D950 ( 2011 ).
  • Cerami E , GaoJ, DogrusozUet al. The cbio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data . Cancer Discov.2 ( 5 ), 401 – 404 ( 2012 ).
  • Cancer Genome Atlas N , AkbaniR . Genomic classification of cutaneous melanoma . Cell161 ( 7 ), 1681 – 1696 ( 2015 ).
  • Hall A , MarshallCJ, SpurrNK, WeissRA . Identification of transforming gene in two human sarcoma cell lines as a new member of the ras gene family located on chromosome 1 . Nature303 ( 5916 ), 396 – 400 ( 1983 ).
  • Shimizu K , GoldfarbM, SuardYet al. Three human transforming genes are related to the viral RAS oncogenes . Proc. Natl Acad. Sci. USA80 ( 8 ), 2112 – 2116 ( 1983 ).
  • Hancock JF . Ras proteins: different signals from different locations . Nat. Rev. Mol. Cell Biol.4 ( 5 ), 373 – 384 ( 2003 ).
  • Buhrman G , HolzapfelG, FeticsS, MattosC . Allosteric modulation of ras positions q61 for a direct role in catalysis . Proc. Natl Acad. Sci. USA107 ( 11 ), 4931 – 4936 ( 2010 ).
  • Adari H , LowyDR, WillumsenBM, DerCJ, MccormickF . Guanosine triphosphatase activating protein (gap) interacts with the p21 ras effector binding domain . Science240 ( 4851 ), 518 – 521 ( 1988 ).
  • Frech M , DardenTA, PedersenLGet al. Role of glutamine–61 in the hydrolysis of gtp by p21h-RAS: an experimental and theoretical study . Biochemistry33 ( 11 ), 3237 – 3244 ( 1994 ).
  • Buhrman G , KumarVS, CiritM, HaughJM, MattosC . Allosteric modulation of RAS-GTP is linked to signal transduction through raf kinase . J. Biol. Chem.286 ( 5 ), 3323 – 3331 ( 2011 ).
  • Johnson L , GreenbaumD, CichowskiKet al. K-ras is an essential gene in the mouse with partial functional overlap with N-ras . Genes Dev.11 ( 19 ), 2468 – 2481 ( 1997 ).
  • Umanoff H , EdelmannW, PellicerA, KucherlapatiR . The murine N-RAS gene is not essential for growth and development . Proc. Natl Acad. Sci. USA92 ( 5 ), 1709 – 1713 ( 1995 ).
  • Koera K , NakamuraK, NakaoKet al. K-ras is essential for the development of the mouse embryo . Oncogene.15 ( 10 ), 1151 – 1159 ( 1997 ).
  • Esteban LM , Vicario-AbejonC, Fernandez-SalgueroPet al. Targeted genomic disruption of H-RAS and N-RAS, individually or in combination, reveals the dispensability of both loci for mouse growth and development . Mol. Cell Biol.21 ( 5 ), 1444 – 1452 ( 2001 ).
  • Perez De Castro I , DiazR, MalumbresMet al. Mice deficient for N-RAS: impaired antiviral immune response and T-cell function . Cancer Res.63 ( 7 ), 1615 – 1622 ( 2003 ).
  • Lassen LB , Ballarin-GonzalezB, SchmitzA, FuchtbauerA, PedersenFS . Fuchtbauer EM. NRAS overexpression results in granulocytosis, T-cell expansion and early lethality in mice . PLoS ONE7 ( 8 ), e42216 ( 2012 ).
  • Johnson DB , SmalleyKS, SosmanJA . Molecular pathways: targeting NRAS in melanoma and acute myelogenous leukemia . Clin. Cancer Res.20 ( 16 ), 4186 – 4192 ( 2014 ).
  • Fedorenko IV , GibneyGT, SmalleyKS . Nras mutant melanoma: biological behavior and future strategies for therapeutic management . Oncogene32 ( 25 ), 3009 – 3018 ( 2013 ).
  • Zipfel PA , BradyDC, KashatusDF, AncrileBD, TylerDS, CounterCM . RAL activation promotes melanomagenesis . Oncogene29 ( 34 ), 4859 – 4864 ( 2010 ).
  • Desideri E , CavalloAL, BaccariniM . Alike but different: RAF paralogs and their signaling outputs . Cell161 ( 5 ), 967 – 970 ( 2015 ).
  • Dumaz N , HaywardR, MartinJet al. In melanoma, Ras mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling . Cancer Res.66 ( 19 ), 9483 – 9491 ( 2006 ).
  • Hatzivassiliou G , SongK, YenIet al. RAF inhibitors prime wild-type raf to activate the mapk pathway and enhance growth . Nature464 ( 7287 ), 431 – 435 ( 2010 ).
  • Poulikakos PI , ZhangC, BollagG, ShokatKM, RosenN . Raf inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF . Nature464 ( 7287 ), 427 – 430 ( 2010 ).
  • Ball NJ , YohnJJ, MorelliJG, NorrisDA, GolitzLE, HoefflerJP . RAS mutations in human melanoma: a marker of malignant progression . J. Invest. Dermatol.102 ( 3 ), 285 – 290 ( 1994 ).
  • Cancer Genome Atlas Network. Electronic Address IMO, Cancer Genome Atlas N . Genomic classification of cutaneous melanoma . Cell161 ( 7 ), 1681 – 1696 ( 2015 ).
  • Siroy AE , BolandGM, MiltonDRet al. Beyond BRAF(v600): clinical mutation panel testing by next-generation sequencing in advanced melanoma . J. Invest. Dermatol.135 ( 2 ), 508 – 515 ( 2015 ).
  • Edlundh-Rose E , EgyhaziS, OmholtKet al. Nras and Braf mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing . Melanoma Res.16 ( 6 ), 471 – 478 ( 2006 ).
  • Cancer Genome Atlas Research N . Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia . N. Engl. J. Med.368 ( 22 ), 2059 – 2074 ( 2013 ).
  • Mardis ER , DingL, DoolingDJet al. Recurring mutations found by sequencing an acute myeloid leukemia genome . N. Engl. J. Med.361 ( 11 ), 1058 – 1066 ( 2009 ).
  • Pylayeva-Gupta Y , GrabockaE, Bar-SagiD . RAS oncogenes: weaving a tumorigenic web . Nat. Rev. Cancer11 ( 11 ), 761 – 774 ( 2011 ).
  • Bos JL . RAS oncogenes in human cancer: a review . Cancer Res.49 ( 17 ), 4682 – 4689 ( 1989 ).
  • Flex E , PetrangeliV, StellaLet al. Somatically acquired Jak1 mutations in adult acute lymphoblastic leukemia . J. Exp. Med.205 ( 4 ), 751 – 758 ( 2008 ).
  • Perentesis JP , BhatiaS, BoyleEet al. RAS oncogene mutations and outcome of therapy for childhood acute lymphoblastic leukemia . Leukemia18 ( 4 ), 685 – 692 ( 2004 ).
  • Zhang J , DingL, HolmfeldtLet al. The genetic basis of early t-cell precursor acute lymphoblastic leukaemia . Nature481 ( 7380 ), 157 – 163 ( 2012 ).
  • Chng WJ , Gonzalez-PazN, Price-TroskaTet al. Clinical and biological significance of RAS mutations in multiple myeloma . Leukemia.22 ( 12 ), 2280 – 2284 ( 2008 ).
  • Bejar R , StevensonK, Abdel-WahabOet al. Clinical effect of point mutations in myelodysplastic syndromes . N. Engl. J. Med.364 ( 26 ), 2496 – 2506 ( 2011 ).
  • Ricci C , FermoE, CortiSet al. RAS mutations contribute to evolution of chronic myelomonocytic leukemia to the proliferative variant . Clin. Cancer Res.16 ( 8 ), 2246 – 2256 ( 2010 ).
  • Ward AF , BraunBS, ShannonKM . Targeting oncogenic RAS signaling in hematologic malignancies . Blood120 ( 17 ), 3397 – 3406 ( 2012 ).
  • Johnson DB , PuzanovI . Treatment of NRAS-mutant melanoma . Curr. Treat. Options Oncol.16 ( 4 ), 15 ( 2015 ).
  • Kelleher FC , McArthurGA . Targeting NRAS in melanoma . Cancer J.18 ( 2 ), 132 – 136 ( 2012 ).
  • Burd CE , LiuW, HuynhMVet al. Mutation-specific ras oncogenicity explains nras codon 61 selection in melanoma . Cancer Discov.4 ( 12 ), 1418 – 1429 ( 2014 ).
  • Zebary A , OmholtK, VassilakiIet al. Kit, NRAS, BRAF and PTEN mutations in a sample of Swedish patients with acral lentiginous melanoma . J Dermatol Sci.72 ( 3 ), 284 – 289 ( 2013 ).
  • Zebary A , JangardM, OmholtK, Ragnarsson-OldingB, HanssonJ . Kit, NRAS and BRAF mutations in sinonasal mucosal melanoma: a study of 56 cases . Br. J. Cancer109 ( 3 ), 559 – 564 ( 2013 ).
  • Van Den Hurk K , BalintB, ToomeySet al. High-throughput oncogene mutation profiling shows demographic differences in BRAF mutation rates among melanoma patients . Melanoma Res.25 ( 3 ), 189 – 199 ( 2015 ).
  • Sheen YS , LiaoYH, LiauJYet al. Prevalence of BRAF and NRAS mutations in cutaneous melanoma patients in taiwan . J. Formos. Med. Assoc.115 ( 2 ), 121 – 127 ( 2016 ).
  • Devitt B , LiuW, SalemiRet al. Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma . Pigment Cell Melanoma Res.24 ( 4 ), 666 – 672 ( 2011 ).
  • Jakob JA , BassettRLJr, NgCSet al. NRAS mutation status is an independent prognostic factor in metastatic melanoma . Cancer118 ( 16 ), 4014 – 4023 ( 2012 ).
  • Carlino MS , HayduLE, KakavandHet al. Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma . Br. J. Cancer111 ( 2 ), 292 – 299 ( 2014 ).
  • Shitaraa D , Tell-MartiG, BadenasCet al. Mutational status of nevus associated-melanomas . Br. J. Dermatol.173 ( 3 ), 671 – 680 ( 2016 ).
  • Hodis E , WatsonIR, KryukovGVet al. A landscape of driver mutations in melanoma . Cell150 ( 2 ), 251 – 263 ( 2012 ).
  • Sensi M , NicoliniG, PettiCet al. Mutually exclusive NRASQ61R and BRAFV600E mutations at the single-cell level in the same human melanoma . Oncogene25 ( 24 ), 3357 – 3364 ( 2006 ).
  • Zebary A , OmholtK, Van DoornRet al. Somatic BRAF and NRAS mutations in familial melanomas with known germline CDKN2A status: a genomel study . J. Invest. Dermatol.134 ( 1 ), 287 – 290 ( 2014 ).
  • Jovanovic B , EgyhaziS, EskandarpourMet al. Coexisting nras and braf mutations in primary familial melanomas with specific CDKN2A germline alterations . J. Invest. Dermatol.130 ( 2 ), 618 – 620 ( 2010 ).
  • Poynter JN , ElderJT, FullenDRet al. BRAF and NRAS mutations in melanoma and melanocytic nevi . Melanoma Res.16 ( 4 ), 267 – 273 ( 2006 ).
  • Charbel C , FontaineRH, MaloufGGet al. NRAS mutation is the sole recurrent somatic mutation in large congenital melanocytic nevi . J. Invest. Dermatol.134 ( 4 ), 1067 – 1074 ( 2014 ).
  • Salgado CM , BasuD, NikiforovaMet al. BRAF mutations are also associated with neurocutaneous melanocytosis and large/giant congenital melanocytic nevi . Pediatr. Dev. Pathol.18 ( 1 ), 1 – 9 ( 2015 ).
  • Massi D , SimiL, SensiEet al. Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma . Mod. Pathol.28 ( 4 ), 487 – 497 ( 2015 ).
  • Ratner N , MillerSJ . A rasopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor . Nat. Rev. Cancer15 ( 5 ), 290 – 301 ( 2015 ).
  • Nissan MH , PratilasCA, JonesAMet al. Loss of NF1 in cutaneous melanoma is associated with ras activation and mek dependence . Cancer Res.74 ( 8 ), 2340 – 2350 ( 2014 ).
  • Maertens O , JohnsonB, HollsteinPet al. Elucidating distinct roles for NF1 in melanomagenesis . Cancer Discov.3 ( 3 ), 338 – 349 ( 2013 ).
  • Wiesner T , KiuruM, ScottSNet al. NF1 mutations are common in desmoplastic melanoma . Am. J. Surg. Pathol. ( 2015 ).
  • Whittaker SR , TheurillatJP, Van AllenEet al. A genome-scale rna interference screen implicates NF1 loss in resistance to raf inhibition . Cancer Discov.3 ( 3 ), 350 – 362 ( 2013 ).
  • Shi H , HugoW, KongXet al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy . Cancer Discov.4 ( 1 ), 80 – 93 ( 2014 ).
  • Van Allen EM , WagleN, SuckerAet al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma . Cancer Discov.4 ( 1 ), 94 – 109 ( 2014 ).
  • Nazarian R , ShiH, WangQet al. Melanomas acquire resistance to b-RAF(V600E) inhibition by RTK or n-RAS upregulation . Nature468 ( 7326 ), 973 – 977 ( 2010 ).
  • Johannessen CM , BoehmJS, KimSYet al. COT drives resistance to raf inhibition through map kinase pathway reactivation . Nature468 ( 7326 ), 968 – 972 ( 2010 ).
  • Wheler J , YelenskyR, FalchookGet al. Next generation sequencing of exceptional responders with BRAF-mutant melanoma: implications for sensitivity and resistance . BMC Cancer15, 61 ( 2015 ).
  • Spagnolo F , GhiorzoP, OrgianoLet al. BRAF-mutant melanoma: treatment approaches, resistance mechanisms, and diagnostic strategies . Onco. Targets Ther.8, 157 – 168 ( 2015 ).
  • Anforth R , MenziesA, BythKet al. Factors influencing the development of cutaneous squamous cell carcinoma in patients on BRAF inhibitor therapy . J. Am. Acad. Dermatol.72 ( 5 ), 809 – 815 e801 ( 2015 ).
  • Anforth R , TembeV, BlumettiT, Fernandez-PenasP . Mutational analysis of cutaneous squamous cell carcinomas and verrucal keratosis in patients taking BRAF inhibitors . Pigment Cell Melanoma Res.25 ( 5 ), 569 – 572 ( 2012 ).
  • Oberholzer PA , KeeD, DziunyczPet al. Ras mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors . J. Clin. Oncol.30 ( 3 ), 316 – 321 ( 2012 ).
  • Johnson DB , PuzanovI . Treatment of NRAS-mutant melanoma . Curr. Treat. Options Oncol.16 ( 4 ), 330 ( 2015 ).
  • Gysin S , SaltM, YoungA, MccormickF . Therapeutic strategies for targeting RAS proteins . Genes Cancer.2 ( 3 ), 359 – 372 ( 2011 ).
  • Konstantinopoulos PA , KaramouzisMV, PapavassiliouAG . Post-translational modifications and regulation of the RAS superfamily of gtpases as anticancer targets . Nat. Rev. Drug Discov.6 ( 7 ), 541 – 555 ( 2007 ).
  • Kohl NE , WilsonFR, MosserSDet al. Protein farnesyltransferase inhibitors block the growth of RAS-dependent tumors in nude mice . Proc. Natl Acad. Sci. USA91 ( 19 ), 9141 – 9145 ( 1994 ).
  • Gajewski TF , SalamaAK, NiedzwieckiDet al. Phase II study of the farnesyltransferase inhibitor r115777 in advanced melanoma (calgb 500104) . J. Transl. Med.10, 246 ( 2012 ).
  • Zhu Z , GolayHG, BarbieDA . Targeting pathways downstream of KRAS in lung adenocarcinoma . Pharmacogenomics15 ( 11 ), 1507 – 1518 ( 2014 ).
  • Ascierto PA , SchadendorfD, BerkingCet al. Mek162 for patients with advanced melanoma harbouring NRAS or val600 braf mutations: a non-randomised, open-label Phase 2 study . Lancet Oncol.14 ( 3 ), 249 – 256 ( 2013 ).
  • Kwong LN , CostelloJC, LiuHet al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma . Nat. Med.18 ( 10 ), 1503 – 1510 ( 2012 ).
  • Sosman Ja KM , LolkemaMet al. A Phase 1b/2 study of lee011 in combination with binimetinib (mek162) in patients with nras-mutant melanoma: early encouraging clinical activity . J. Clin. Oncol.32 ( 5s ), 2014 ( suppl; abstr 9009 ) ( 2014 ).
  • Jaiswal BS , JanakiramanV, KljavinNMet al. Combined targeting of BRAF and CRAF or BRAF and PI3K effector pathways is required for efficacy in nras mutant tumors . PLoS ONE4 ( 5 ), e5717 ( 2009 ).
  • Posch C , MoslehiH, FeeneyLet al. Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo . Proc. Natl Acad. Sci. USA110 ( 10 ), 4015 – 4020 ( 2013 ).
  • Clinicaltrials database: NCT01781572 . https://clinicaltrials.Gov/ct2/show/nct01781572 .
  • Clinicaltrials database: NCT02065063 . https://clinicaltrials.Gov/ct2/show/nct02065063 .
  • Clinicaltrials database: NCT01363232 . https://clinicaltrials.Gov/ct2/show/nct01363232 .
  • Clinicaltrials database: NCT01337765 . https://clinicaltrials.Gov/ct2/show/nct01337765 .
  • Clinicaltrials database: NCT01449058 . https://clinicaltrials.Gov/ct2/show/nct01449058 .
  • Clinicaltrials database: NCT01941927 . https://clinicaltrials.Gov/ct2/show/nct01941927 .
  • Clinicaltrials database: NCT01693068 . https://clinicaltrials.Gov/ct2/show/nct01693068 .
  • Clinicaltrials database: NCT01763164 . https://clinicaltrials.Gov/ct2/show/nct01763164 .
  • Clinicaltrials database: NCT01352273 . https://clinicaltrials.Gov/ct2/show/nct01352273 .
  • Posch C , MoslehiH, FeeneyLet al. Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo . Proc. Natl Acad. Sci. USA110 ( 10 ), 4015 – 4020 ( 2013 ).
  • Greger JG , EastmanSD, ZhangVet al. Combinations of BRAF, MEK, and PI3K/MTOR inhibitors overcome acquired resistance to the BRAF inhibitor gsk2118436 dabrafenib, mediated by NRAS or MEK mutations . Mol. Cancer Ther.11 ( 4 ), 909 – 920 ( 2012 ).
  • Takashima A , EnglishB, ChenZet al. Protein kinase cdelta is a therapeutic target in malignant melanoma with NRAS mutation . ACS Chem. Biol.9 ( 4 ), 1003 – 1014 ( 2014 ).
  • Chattopadhyay C , EllerhorstJA, EkmekciogluS, GreeneVR, DaviesMA, GrimmEA . Association of activated c-Met with NRAS-mutated human melanomas . Int. J. Cancer131 ( 2 ), E56 – 65 ( 2012 ).
  • Atefi M , TitzB, AvramisEet al. Combination of pan-RAF and MEK inhibitors in NRAS mutant melanoma . Mol. Cancer.14, 27 ( 2015 ).
  • Le K , BlomainES, RodeckU, AplinAE . Selective raf inhibitor impairs ERK1/2 phosphorylation and growth in mutant NRAS, vemurafenib-resistant melanoma cells . Pigment. Cell Melanoma Res.26 ( 4 ), 509 – 517 ( 2013 ).
  • Wong DJ , RobertL, AtefiMSet al. Antitumor activity of the ERK inhibitor sch722984 against BRAF mutant, NRAS mutant and wild-type melanoma . Mol Cancer.13, 194 ( 2014 ).
  • Fedorenko IV , FangB, KoomenJM, GibneyGT, SmalleyKS . Amuvatinib has cytotoxic effects against NRAS-mutant melanoma but not braf-mutant melanoma . Melanoma Res.24 ( 5 ), 448 – 453 ( 2014 ).
  • Haarberg HE , ParaisoKH, WoodEet al. Inhibition of Wee1, Akt, and Cdk4 underlies the efficacy of the Hsp90 inhibitor xl888 in an in vivo model of NRAS-mutant melanoma . Mol Cancer Ther.12 ( 6 ), 901 – 912 ( 2013 ).
  • Rosenberg SA , NiglioSA, SalehomoumNet al. Targeting glutamatergic signaling and the PI3 kinase pathway to halt melanoma progression . Transl Oncol.8 ( 1 ), 1 – 9 ( 2015 ).
  • Vu HL , AplinAE . Targeting Tbk1 inhibits migration and resistance to MEK inhibitors in mutant NRAS melanoma . Mol. Cancer Res.12 ( 10 ), 1509 – 1519 ( 2014 ).
  • Weisberg E , NonamiA, ChenZet al. Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies . Leukemia.29 ( 1 ), 27 – 37 ( 2015 ).
  • Vogel CJ , SmitMA, MaddaloGet al. Cooperative induction of apoptosis in NRAS mutant melanoma by inhibition of MEK and rock . Pigment Cell Melanoma Res.28 ( 3 ), 307 – 317 ( 2015 ).
  • Posch C , CholewaBD, VujicIet al. Combined inhibition of MEK and plk1 has synergistic antitumor activity in NRAS mutant melanoma . J. Invest. Dermatol.135 ( 10 ), 2475 – 2483 ( 2015 ).
  • Yang Y , WuJ, DemirAet al. Gab2 induces tumor angiogenesis in NRAS-driven melanoma . Oncogene32 ( 31 ), 3627 – 3637 ( 2013 ).
  • Feng Y , LauE, ScortegagnaMet al. Inhibition of melanoma development in the nras((q61k)): Ink4a(-/-) mouse model by the small molecule bi–69a11 . Pigment Cell Melanoma Res.26 ( 1 ), 136 – 142 ( 2013 ).
  • Vujic I , SanlorenzoM, PoschCet al. Metformin and trametinib have synergistic effects on cell viability and tumor growth in NRAS mutant cancer . Oncotarget6 ( 2 ), 969 – 978 ( 2015 ).
  • Carbognin L , PilottoS, MilellaMet al. Differential activity of nivolumab, pembrolizumab and mpdl3280a according to the tumor expression of programmed death-ligand–1 (PD-L1): sensitivity analysis of trials in melanoma, lung and genitourinary cancers . PLoS ONE10 ( 6 ), e0130142 ( 2015 ).
  • Topalian SL , HodiFS, BrahmerJRet al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer . N. Engl. J. Med.366 ( 26 ), 2443 – 2454 ( 2012 ).
  • Atefi M , AvramisE, LassenAet al. Effects of mapk and PI3K pathways on PD-L1 expression in melanoma . Clin. Cancer Res.20 ( 13 ), 3446 – 3457 ( 2014 ).
  • Joseph RW , SullivanRJ, HarrellRet al. Correlation of NRAS mutations with clinical response to high-dose IL-2 in patients with advanced melanoma . J. Immunother.35 ( 1 ), 66 – 72 ( 2012 ).
  • Johnson DB , LovlyCM, FlavinMet al. Impact of nras mutations for patients with advanced melanoma treated with immune therapies . Cancer Immunol. Res.3 ( 3 ), 288 – 295 ( 2015 ).
  • Varada S , MahalingamM . Mutation stability in primary and metastatic melanoma: what we know and what we don't . Histol. Histopathol.30 ( 7 ), 763 – 770 ( 2015 ).
  • Van Allen EM , GolayHG, LiuYet al. Long-term benefit of PD-L1 blockade in lung cancer associated with Jak3 activation . Cancer Immunol Res.3 ( 8 ), 855 – 863 ( 2015 ).
  • Tomei S , BedognettiD, De GiorgiVet al. The immune-related role of BRAF in melanoma . Mol. Oncol.9 ( 1 ), 93 – 104 ( 2015 ).
  • Cooper ZA , JunejaVR, SagePTet al. Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade . Cancer Immunol. Res.2 ( 7 ), 643 – 654 ( 2014 ).
  • Ribas A , HodiFS, CallahanM, KontoC, WolchokJ . Hepatotoxicity with combination of vemurafenib and ipilimumab . N. Engl. J. Med.368 ( 14 ), 1365 – 1366 ( 2013 ).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.