Novel insights into the pathogenesis and treatment of NRAS mutant melanoma

References

• Hocker T, Tsao H. Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants. Hum Mutat. 2007;28(6):578–588.
   PubMed Web of Science ®Google Scholar
• Singh M, Lin J, Hocker T, et al. Genetics of melanoma tumorigenesis. Br J Dermatol. 2008;158(1):15–21.
   PubMed Web of Science ®Google Scholar
• Van ‘T Veer LJ, Burgering BM, Versteeg R, et al. N-ras mutations in human cutaneous melanoma from sun-exposed body sites. Molecular and Cellular Biology. 1989;9(7):3114–3116.
   PubMed Web of Science ®Google Scholar
• Ball NJ, Yohn JJ, Morelli JG, et al. RAS Mutations in Human Melanoma: a Marker of Malignant Progression. J Invest Dermatol. 1994;102(3):285–290.
   PubMed Web of Science ®Google Scholar
• Platz A, Sevigny P, Norberg T, et al. Genes involved in cell cycle G1 checkpoint control are frequently mutated in human melanoma metastases. Br J Cancer. 1996;74(6):936–941.
   PubMed Web of Science ®Google Scholar
• van Elsas A, Zerp SF, van der Flier S, et al. Relevance of ultraviolet-induced N-ras oncogene point mutations in development of primary human cutaneous melanoma. Am J Pathol. 1996;149(3):883.
   PubMed Web of Science ®Google Scholar
• Jiveskog S, Ragnarsson-Olding B, Platz A, et al. N-ras mutations are common in melanomas from sun-exposed skin of humans but rare in mucosal membranes or unexposed skin. J Invest Dermatol. 1998;111(5):757–761.
   PubMed Web of Science ®Google Scholar
• Omholt K, Karsberg S, Platz A, et al. Screening of N-ras codon 61 mutations in paired primary and metastatic cutaneous melanomas: mutations occur early and persist throughout tumor progression. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. 2002;8(11):3468–3474.
   PubMed Web of Science ®Google Scholar
• Akbani R, Akdemir KC, Aksoy BA, et al. Genomic classification of cutaneous melanoma. Cell. 2015;161(7):1681–1696.
   PubMed Web of Science ®Google Scholar
• Gorden A, Osman I, Gai W, et al. Analysis of BRAF and N-RAS mutations in metastatic melanoma tissues. Cancer Res. 2003;63(14):3955–3957.
   PubMed Web of Science ®Google Scholar
• Stas M, Degreef H, Demunter A, et al. Analysis of N-and K-ras mutations in the distinctive tumor progression phases of melanoma. J Invest Dermatol. 2001;117(6):1483–1489.
   PubMed Web of Science ®Google Scholar
• Tsao H, Chin L, Garraway LA, et al. Melanoma: from mutations to medicine. Genes Dev. 2012;26(11):1131–1155.
   PubMed Web of Science ®Google Scholar
• Johnson DB, Chandra S, Sosman JA. Immune Checkpoint Inhibitor Toxicity in 2018. JAMA. 2018;320(16):1702–1703.
   PubMed Web of Science ®Google Scholar
• Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med. 2018;378(2):158–168.
   PubMed Web of Science ®Google Scholar
• Mangan BL, McAlister RK, Balko JM, et al. Evolving insights into the mechanisms of toxicity associated with immune checkpoint inhibitor therapy. Br J Clin Pharmacol. 2020;86(9):1778–1789.
   PubMed Web of Science ®Google Scholar
• Costa R, Carneiro BA, Agulnik M, et al. Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials. Oncotarget. 2017 Jan 31;8(5):8910–8920.
   PubMedGoogle Scholar
• Wang DY, Mooradian MJ, Kim D, et al. Clinical characterization of colitis arising from anti-PD-1 based therapy. Oncoimmunology. 2019;8(1):e1524695.
   PubMed Web of Science ®Google Scholar
• Padua R, Barrass NC, Currie GA. Activation of N-ras in a human melanoma cell line. Mol Cell Biol. 1985;5(3):582–585.
   PubMed Web of Science ®Google Scholar
• Cooper GM. Cellular transforming genes. Science. 1982;217(4562):801–806.
   PubMed Web of Science ®Google Scholar
• Padua R, Barrass N, Currie G. A novel transforming gene in a human malignant melanoma cell line. Nature. 1984;311(5987):671–673.
   PubMed Web of Science ®Google Scholar
• Cox AD, Der CJ. Ras history. Small GTPases. 2010;1(1):2–27. 2010 2010/07/01.
   PubMedGoogle Scholar
• Albino AP, Le Strange R, Oliff AI, et al. Transforming ras genes from human melanoma: a manifestation of tumour heterogeneity? Nature. 1984;308(5954):69–72.
   PubMed Web of Science ®Google Scholar
• Akbani, Rehan, Kadir CA, et al. Genomic Classification of Cutaneous Melanoma. Cell. Cell. 2015 Jun 18;161(7):1681–1696.
   PubMed Web of Science ®Google Scholar
• Sanchez-Vega F, Mina M, Armenia J, et al. Oncogenic Signaling Pathways in The Cancer Genome Atlas. Cell. 2018;173(2):321-337.
   Google Scholar
• Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012;72(10):2457–2467.
   PubMed Web of Science ®Google Scholar
• Hobbs GA, Der CJ, Rossman KL. RAS isoforms and mutations in cancer at a glance. J Cell Sci. 2016;129(7):1287–1292.
   PubMed Web of Science ®Google Scholar
• Turner N, Ware O, Bosenberg M. Genetics of metastasis: melanoma and other cancers. Clin Exp Metastasis. 2018;35(5):379–391. 2018 2018/08/01.
   PubMed Web of Science ®Google Scholar
• Goydos JS, Mann B, Kim HJ, et al. Detection of B-RAF and N-RAS mutations in human melanoma. J Am Coll Surg. 2005;200(3):362–370.
   PubMed Web of Science ®Google Scholar
• Simanshu DK, Nissley DV, McCormick F. RAS Proteins and Their Regulators in Human Disease. Cell. 2017 Jun 29;170(1):17–33.
   PubMed Web of Science ®Google Scholar
• Nussinov R, Tsai C-J, Chakrabarti M, et al. A New View of Ras Isoforms in Cancers. Cancer Res. 2016 Jan 1;76(1):18–23.
   PubMed Web of Science ®Google Scholar
• Edlundh-Rose E, Egyha S, Omholt K, et al. NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. Melanoma Res. 2006;16(6):471–478.
   PubMed Web of Science ®Google Scholar
• Goel VK, Lazar AJF, Warneke CL, et al. Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J Invest Dermatol. 2006;126(1):154–160.
   PubMed Web of Science ®Google Scholar
• Devitt B, Liu W, Salemi R, et al. Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma. Pigment Cell Melanoma Res. 2011;24(4):666–672.
   PubMed Web of Science ®Google Scholar
• Berger MF, Hodis E, Heffernan TP, et al. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature. 2012;485(7399):502–506.
   PubMed Web of Science ®Google Scholar
• Colombino M, Capone M, Lissia A, et al. BRAF/NRAS Mutation Frequencies Among Primary Tumors and Metastases in Patients With Melanoma. J Clin Oncol. 2012;30(20):2522–2529.
   PubMed Web of Science ®Google Scholar
• Sensi M, Nicolini G, Petti C, et al. Mutually exclusive NRASQ61R and BRAFV600E mutations at the single-cell level in the same human melanoma. Oncogene. 2006;25(24):3357–3364.
   PubMed Web of Science ®Google Scholar
• Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002 06 01;417(6892):949–954.
   PubMed Web of Science ®Google Scholar
• Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135–2147.
   PubMed Web of Science ®Google Scholar
• Ticha I, Hojny J, Michalkova R, et al. A comprehensive evaluation of pathogenic mutations in primary cutaneous melanomas, including the identification of novel loss-of-function variants. Sci Rep. 2019 11 19;9(1):17050.
   PubMedGoogle Scholar
• Elder DE, Bastian BC, Cree IA, et al. The 2018 World Health Organization Classification of Cutaneous, Mucosal, and Uveal Melanoma: detailed Analysis of 9 Distinct Subtypes Defined by Their Evolutionary Pathway. Arch Pathol Lab Med. 2020 Apr;144(4):500–522.
   PubMed Web of Science ®Google Scholar
• Wu H, Goel V, Haluska FG. PTEN signaling pathways in melanoma. Oncogene. 2003;22(20):3113–3122.
   PubMed Web of Science ®Google Scholar
• Tsao H, Yang G, Goel V, et al. Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol. 2004;122(2):337–341.
   PubMed Web of Science ®Google Scholar
• Jakob JA, Bassett JRL, Ng CS, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2012;118(16):4014–4023.
   PubMed Web of Science ®Google Scholar
• Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009 Apr 9;458(7239):719–724.
   PubMed Web of Science ®Google Scholar
• Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure. European Journal of Cancer. 2005 Jan;41(1):45–60.
   PubMed Web of Science ®Google Scholar
• Platz A, Egyhazi S, Ringborg U, et al. Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site. Mol Oncol. 2008;1(4):395–405.
   PubMed Web of Science ®Google Scholar
• Hennessey RC, Holderbaum AM, Bonilla A, et al. Ultraviolet radiation accelerates NRas-mutant melanomagenesis: a cooperative effect blocked by sunscreen. Pigment Cell Melanoma Res. 2017 Sep;30(5):477–487.
   PubMed Web of Science ®Google Scholar
• Mor A, Philips MR. COMPARTMENTALIZED RAS/MAPK SIGNALING. Annu Rev Immunol. 2006;24(1):771–800.
   PubMedGoogle Scholar
• Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell. 2012;150(2):251–263.
   PubMed Web of Science ®Google Scholar
• Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3(6):459–465.
   PubMed Web of Science ®Google Scholar
• Burd CE, Liu W, Huynh MV, et al. Mutation-Specific RAS Oncogenicity Explains NRAS Codon 61 Selection in Melanoma. Cancer Discov. 2014;4(12):1418–1429.
   PubMed Web of Science ®Google Scholar
• Jonsson A, Tuominen R, Grafström E, et al. High Frequency of p16INK4A Promoter Methylation in NRAS-Mutated Cutaneous Melanoma. J Invest Dermatol. 2010;130(12):2809–2817.
   PubMed Web of Science ®Google Scholar
• Clark WH, Elder DE, Guerry D, et al. A study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. Hum Pathol. 1984 12 01;15(12):1147–1165.
   PubMed Web of Science ®Google Scholar
• Martincorena I, Roshan A, Gerstung M, et al. High burden and pervasive positive selection of somatic mutations in normal human skin. Science. 2015;348(6237):880–886.
   PubMed Web of Science ®Google Scholar
• Tang J, Fewings E, Chang D, et al. The genomic landscapes of individual melanocytes from human skin. Nature. 2020 10 01;586(7830):600–605.
   PubMed Web of Science ®Google Scholar
• Shain AH, Yeh I, Kovalyshyn I, et al. The Genetic Evolution of Melanoma from Precursor Lesions. N Engl J Med. 2015;373(20):1926–1936.
   PubMed Web of Science ®Google Scholar
• Kraehn GM, Utikal J, Udart M, et al. Extra c-myc oncogene copies in high risk cutaneous malignant melanoma and melanoma metastases. Br J Cancer. 2001 Jan 5;84(1):72–79.
   PubMed Web of Science ®Google Scholar
• Zhuang D, Mannava S, Grachtchouk V, et al. C-MYC overexpression is required for continuous suppression of oncogene-induced senescence in melanoma cells. Oncogene. 2008 11 01;27(52):6623–6634.
   PubMed Web of Science ®Google Scholar
• Giuliano S, Ohanna M, Ballotti R, et al. Advances in melanoma senescence and potential clinical application. Pigment Cell Melanoma Res. 2011;24(2):295–308.
   PubMed Web of Science ®Google Scholar
• Shitara D, Tell-Martí G, Badenas C, et al. Mutational status of naevus-associated melanomas. Br J Dermatol. 2015;173(3):671–680.
   PubMed Web of Science ®Google Scholar
• Tan J-M, Lin LL, Lambie D, et al. BRAF Wild-Type Melanoma in Situ Arising In a BRAF V600E Mutant Dysplastic Nevus. JAMA Dermatol. 2015;151(4):417–421.
   PubMed Web of Science ®Google Scholar
• Bauer J, Curtin JA, Pinkel D, et al. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol. 2007;127(1):179–182.
   PubMed Web of Science ®Google Scholar
• Kinsler VA, Thomas AC, Ishida M, et al. Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS. J Invest Dermatol. 2013;133(9):2229–2236.
   PubMed Web of Science ®Google Scholar
• Gerami P, Paller AS. Making a mountain out of a molehill: NRAS, mosaicism, and large congenital nevi. J Invest Dermatol. 2013 Sep;133(9):2127–2130.
   PubMed Web of Science ®Google Scholar
• Hayward NK, Wilmott JS, Waddell N, et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017;545(7653):175–180.
   PubMed Web of Science ®Google Scholar
• Yan J, Wu X, Yu J, et al. Analysis of NRAS gain in 657 patients with melanoma and evaluation of its sensitivity to a MEK inhibitor. Eur J Cancer. 2018;89:90–101.
   PubMed Web of Science ®Google Scholar
• Omholt K, Platz A, Kanter L, et al. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. 2003;9(17):6483–6488.
   PubMed Web of Science ®Google Scholar
• Viros A, Fridlyand J, Bauer J, et al. Improving melanoma classification by integrating genetic and morphologic features. PLoS Med. 2008 Jun 3;5(6):e120.
   PubMed Web of Science ®Google Scholar
• Lee J-H, Choi J-W, Kim Y-S. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol. 2011 Apr;164(4):776–784.
   PubMed Web of Science ®Google Scholar
• Gutiérrez-Castañeda LD, Nova JA, Tovar-Parra JD. Frequency of mutations in BRAF, NRAS, and KIT in different populations and histological subtypes of melanoma: a systemic review. Melanoma Res. 2020;30(1):62.
   PubMed Web of Science ®Google Scholar
• Davis EJ, Johnson DB, Sosman JA, et al. Melanoma: what do all the mutations mean? Cancer. 2018 Sep 1;124(17):3490–3499.
   PubMed Web of Science ®Google Scholar
• Davis AA, McKee AE, Kibbe WA, et al. Complexity of Delivering Precision Medicine: opportunities and Challenges. Am Soc Clin Oncol Educ Book. 2018 May;23(38):998–1007.
   Google Scholar
• Nagler A, Vredevoogd DW, Alon M, et al. A genome-wide CRISPR screen identifies FBXO42 involvement in resistance toward MEK inhibition in NRAS -mutant melanoma. Pigment Cell Melanoma Res. 2020;33(2):334–344.
   PubMed Web of Science ®Google Scholar
• Welsch ME, Kaplan A, Chambers JM, et al. Multivalent small-molecule pan-RAS inhibitors. Cell. 2017;168(5):878–889. e29.
   PubMed Web of Science ®Google Scholar
• Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019 11 01;575(7781):217–223.
   PubMed Web of Science ®Google Scholar
• Hong DS, Fakih MG, Strickler JH, et al. KRAS G12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med. 2020;383(13):1207–1217.
   PubMed Web of Science ®Google Scholar
• Kim D, Xue JY, Lito LP. Targeting KRAS(G12C): from Inhibitory Mechanism to Modulation of Antitumor Effects in Patients. Cell. 2020 11 12;183(4):850–859.
   PubMed Web of Science ®Google Scholar
• Martinko AJ, Truillet C, Julien O, et al. Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins. Elife.2018;Jan:Vol. 23;7:e31098.
   Google Scholar
• Guillard S, Kolasinska-Zwierz P, Debreczeni J, et al. Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange. Nat Commun. 2017 07 14;8(1):16111.
   PubMedGoogle Scholar
• Shin S-M, Kim J-S, Park S-W, et al. Direct targeting of oncogenic RAS mutants with a tumor-specific cytosol-penetrating antibody inhibits RAS mutant–driven tumor growth. Sci Adv. 2020;6(3):eaay2174.
   PubMed Web of Science ®Google Scholar
• Zimmer L, Barlesi F, Martinez-Garcia M, et al. Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with <em>RAS-RAF mutations. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. 2014;20(16):4251–4261.
   PubMed Web of Science ®Google Scholar
• Moore AR, Rosenberg SC, McCormick F, et al. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020;19(8):533–552.
   Web of Science ®Google Scholar
• Murphy BM, Burd CE. Can combination MEK and Akt inhibition slay the Giant congenital nevus? J Invest Dermatol. 2019;139(9):1857–1859.
   PubMed Web of Science ®Google Scholar
• Kinsler VA, O’Hare P, Jacques T, et al. MEK inhibition appears to improve symptom control in primary NRAS-driven CNS melanoma in children. Br J Cancer. 2017;116(8):990–993.
   PubMed Web of Science ®Google Scholar
• Rouillé T, Aractingi S, Kadlub N, et al. Local Inhibition of MEK/Akt Prevents Cellular Growth in Human Congenital Melanocytic Nevi. J Invest Dermatol. 2019 09 01;139(9):2004–2015.e13.
   PubMedGoogle Scholar
• Solit DB, Garraway LA, Pratilas CA, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439(7074):358–362.
   PubMed Web of Science ®Google Scholar
• Von Euw E, Atefi M, Attar N, et al. Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines. Molecular Cancer. 2012;11(1):22.
   PubMedGoogle Scholar
• Boasberg PD, Redfern CH, Daniels GA, et al. Pilot study of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer. Cancer Chemother Pharmacol. 2011 Aug;68(2):547–552.
   PubMed Web of Science ®Google Scholar
• LoRusso PM, Krishnamurthi SS, Rinehart JJ, et al. Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral MAPK/ERK Kinase Inhibitor PD-0325901 in Patients with Advanced Cancers. Clin Cancer Res. 2010;16(6):1924–1937.
   PubMed Web of Science ®Google Scholar
• Niessner H, Sinnberg T, Kosnopfel C, et al. BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma. Clin Cancer Res. 2017 Oct 15;23(20):6203–6214.
   PubMed Web of Science ®Google Scholar
• Banik I, Cheng PF, Dooley CM, et al. NRASQ61K melanoma tumor formation is reduced by p38-MAPK14 activation in zebrafish models and NRAS-mutated human melanoma cells. Pigment Cell & Melanoma Research. n/a(n/a).
   Google Scholar
• De Jong PR, Taniguchi K, Harris AR, et al. ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation. Nat Commun. 2016;7(1):1–15.
   Google Scholar
• Adam C, Fusi L, Weiss N, et al. Efficient suppression of NRAS-driven melanoma by co-inhibition of ERK1/2 and ERK5 MAPK pathways. J Invest Dermatol. 2020;140(12):2455–2465.e10.
   Web of Science ®Google Scholar
• Tusa I, Gagliardi S, Tubita A, et al. ERK5 is activated by oncogenic BRAF and promotes melanoma growth. Oncogene. 2018;37(19):2601–2614.
   PubMed Web of Science ®Google Scholar
• Lin ECK, Amantea CM, Nomanbhoy TK, et al. ERK5 kinase activity is dispensable for cellular immune response and proliferation. Proc Nat Acad Sci. 2016 113;(42)11865–11870.
   PubMed Web of Science ®Google Scholar
• Lee B, McArthur GA. CDK4 inhibitors an emerging strategy for the treatment of melanoma. Melanoma Manag. 2015 Aug;2(3):255–266.
   PubMed Web of Science ®Google Scholar
• Griewank KG, Scolyer RA, Thompson JF, et al. Genetic Alterations and Personalized Medicine in Melanoma: progress and Future Prospects. JNCI Journal of the National Cancer Institute. 2014;106(2):2.
   Google Scholar
• Sharma S, Zhang T, Michowski W, et al. Targeting the cyclin-dependent kinase 5 in metastatic melanoma. Proc Nat Acad Sci. 2020 117;(14)8001–8012.
   PubMed Web of Science ®Google Scholar
• Sellers WR, Kaelin JWG. Role of the retinoblastoma protein in the pathogenesis of human cancer. J Clin Oncol. 1997;15(11):3301–3312.
   PubMed Web of Science ®Google Scholar
• Puig-Butille JA, Vinyals A, Ferreres JR, et al. AURKA overexpression is driven by FOXM1 and MAPK/ERK activation in melanoma cells harboring BRAF or NRAS mutations: impact on melanoma prognosis and therapy. J Invest Dermatol. 2017;137(6):1297–1310.
   PubMed Web of Science ®Google Scholar
• Ahmed RL, Shaughnessy DP, Knutson TP, et al. CDK11 Loss Induces Cell Cycle Dysfunction and Death of BRAF and NRAS Melanoma Cells. Pharmaceuticals. 2019;12(2):50.
   Web of Science ®Google Scholar
• Kwong LN, Costello JC, Liu H, et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med. 2012 10 01;18(10):1503–1510.
   PubMed Web of Science ®Google Scholar
• Zhang J, Bu X, Wang H, et al. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature. 2018 Jan 4;553(7686):91–95.
   PubMed Web of Science ®Google Scholar
• Zhang J, Bu X, Wang H, et al. Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance. Nature. 2018 01 01;553(7686):91–95. 10.1038/nature25015.
   PubMed Web of Science ®Google Scholar
• Goel S, DeCristo MJ, Watt AC, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017 08 01;548(7668):471–475.
   PubMed Web of Science ®Google Scholar
• Yu J, Yan J, Guo Q, et al. Genetic Aberrations in the CDK4 Pathway Are Associated with Innate Resistance to PD-1 Blockade in Chinese Patients with Non-Cutaneous Melanoma. Clin Cancer Res. 2019;25(21):6511–6523.
   PubMed Web of Science ®Google Scholar
• Posch C, Moslehi H, Feeney L, et al. Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo. Proc Nat Acad Sci. 2013;110(10):4015–4020.
   PubMed Web of Science ®Google Scholar
• Bryant KL, Stalnecker CA, Zeitouni D, et al. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat Med. 2019 04 01;25(4):628–640.
   PubMed Web of Science ®Google Scholar
• Kinsey CG, Camolotto SA, Boespflug AM, et al. Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med. 2019 Apr;25(4):620–627.
   PubMed Web of Science ®Google Scholar
• Rusch M, Zimmermann TJ, Bürger M, et al. Identification of acyl protein thioesterases 1 and 2 as the cellular targets of the Ras‐signaling modulators palmostatin B and M. Angewandte Chemie. 2011;50(42):9838–9842.
   Google Scholar
• Appels NM, Beijnen JH, Schellens JH. Development of farnesyl transferase inhibitors: a review. Oncologist. 2005;10(8):565–578.
   PubMed Web of Science ®Google Scholar
• Rocks O, Peyker A, Kahms M, et al. An acylation cycle regulates localization and activity of palmitoylated Ras isoforms. Science. 2005;307(5716):1746–1752.
   PubMed Web of Science ®Google Scholar
• Vigil D, Cherfils J, Rossman KL, et al. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer. 2010;10(12):842–857.
   PubMed Web of Science ®Google Scholar
• Vilgelm AE, Saleh N, Shattuck-Brandt R, et al. MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21. Sci Transl Med. 2019;11(505):eaav7171.
   PubMed Web of Science ®Google Scholar
• Gajewski TF, Salama AK, Niedzwiecki D, et al. Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104). J Transl Med. 2012;10(1):246.
   PubMedGoogle Scholar
• Hussain J, Kirubakaran S, Ravi S. The Endeavours in RAS Inhibition-the Past, Present, and Future. Curr Top Med Chem. 2020;20(29):2708–2722.
   Web of Science ®Google Scholar
• Vora HD, Johnson M, Brea RJ, et al. Inhibition of NRAS Signaling in Melanoma through Direct Depalmitoylation Using Amphiphilic Nucleophiles. ACS Chem Biol. 2020;15(8):2079–2086.
   PubMed Web of Science ®Google Scholar
• Goodwin JS, Drake KR, Rogers C, et al. Depalmitoylated Ras traffics to and from the Golgi complex via a nonvesicular pathway. J Cell Biol. 2005;170(2):261–272.
   PubMed Web of Science ®Google Scholar
• Reyes-Uribe P, Adrianzen-Ruesta MP, Deng Z, et al. Exploiting TERT dependency as a therapeutic strategy for NRAS-mutant melanoma. Oncogene. 2018;37(30):4058–4072.
   PubMed Web of Science ®Google Scholar
• Bussenius J, Blazey CM, Aay N, et al. Discovery of XL888: a novel tropane-derived small molecule inhibitor of HSP90. Bioorg Med Chem Lett. 2012 09 01;22(17):5396–5404.
   PubMed Web of Science ®Google Scholar
• Haarberg HE, Paraiso KHT, Wood E, et 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. 2013;12(6):901–912.
   PubMed Web of Science ®Google Scholar
• Shah A, Delgado-Goni T, Casals Galobart T, et al. Detecting human melanoma cell re-differentiation following BRAF or heat shock protein 90 inhibition using photoacoustic and magnetic resonance imaging. Sci Rep. 2017 08 15;7(1):8215.
   PubMedGoogle Scholar
• Siu KS, Chen D, Zheng X, et al. Non-covalently functionalized single-walled carbon nanotube for topical siRNA delivery into melanoma. Biomaterials. 2014 03 01;35(10):3435–3442.
   PubMed Web of Science ®Google Scholar
• Labala S, Jose A, Venuganti VVK. Transcutaneous iontophoretic delivery of STAT3 siRNA using layer-by-layer chitosan coated gold nanoparticles to treat melanoma. Colloids Surf B Biointerfaces. 2016 10 01;146:188–197.
   PubMed Web of Science ®Google Scholar
• Shi J, Kantoff PW, Wooster R, et al. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2017 01 01;17(1):20–37.
   PubMed Web of Science ®Google Scholar
• Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020;383(27):2603–2615.
   PubMed Web of Science ®Google Scholar
• Walsh EE, Frenck RW, Falsey AR, et al. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. N Engl J Med. 2020;383(25):2439–2450.
   PubMed Web of Science ®Google Scholar
• Mulligan MJ, Lyke KE, Kitchin N, et al. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature. 2020 10 01;586(7830):589–593.
   PubMed Web of Science ®Google Scholar
• Davis ME, Zuckerman JE, Choi CH, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature. 2010 Apr 15;464(7291):1067–1070.
   PubMed Web of Science ®Google Scholar
• Yi X, Zhao G, Zhang H, et al. MITF-siRNA Formulation Is a Safe and Effective Therapy for Human Melasma. Mol Ther. 2011 02 01;19(2):362–371.
   PubMed Web of Science ®Google Scholar
• Kaplan F, Shao Y, Mayberry M, et al. Hyperactivation of MEK–ERK1/2 signaling and resistance to apoptosis induced by the oncogenic b-RAF inhibitor, PLX4720, in mutant n-RAS melanoma cells. Oncogene. 2011;30(3):366–371.
   PubMed Web of Science ®Google Scholar
• Halaban R, Zhang W, Bacchiocchi A, et al. PLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAFWT melanoma cells. Pigment Cell Melanoma Res. 2010;23(2):190–200.
   PubMed Web of Science ®Google Scholar
• Weeraratna AT. RAF around the edges–the paradox of BRAF inhibitors. N Engl J Med. 2012;366(3):271–273.
   PubMed Web of Science ®Google Scholar
• Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140(2):209–221.
   PubMed Web of Science ®Google Scholar
• Hartsough EJ, Kugel CH, Vido MJ, et al. Response and resistance to paradox-breaking BRAF inhibitor in melanomas in vivo and ex vivo. Mol Cancer Ther. 2018;17(1):84–95.
   PubMed Web of Science ®Google Scholar
• Dummer R, Schadendorf D, Ascierto PA, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(4):435–445.
   PubMed Web of Science ®Google Scholar
• Queirolo P, Spagnolo F. Binimetinib for the treatment of NRAS-mutant melanoma. Expert Rev Anticancer Ther. 2017;17(11):985–990.
   PubMed Web of Science ®Google Scholar
• Algazi AP, Esteve-Puig R, Nosrati A, et al. Dual MEK/AKT inhibition with trametinib and GSK2141795 does not yield clinical benefit in metastatic NRAS-mutant and wild-type melanoma. Pigment Cell Melanoma Res. 2005;10(8):110–114.
   Google Scholar
• Germann UA, Furey BF, Markland W, et al. Targeting the MAPK Signaling Pathway in Cancer: promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib). Mol Cancer Ther. 2017 Nov;16(11):2351–2363.
   PubMed Web of Science ®Google Scholar
• Sullivan RJ, Infante JR, Janku F, et al. 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. 2018;8(2):184–195.
   PubMed Web of Science ®Google Scholar
• Moschos SJ, Sullivan RJ, Hwu WJ, et al. Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors. JCI Insight. 2018 Feb 22;3(4):4.
   Web of Science ®Google Scholar
• Mak G, Soria JC, Blagden SP, et al. A phase Ib dose-finding, pharmacokinetic study of the focal adhesion kinase inhibitor GSK2256098 and trametinib in patients with advanced solid tumours. Br J Cancer. 2019 May;120(10):975–981.
   PubMed Web of Science ®Google Scholar
• Ozkan-Dagliyan I, Diehl JN, George SD, et al. Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers. Cell Rep. 2020 Jun 16;31(11):107764.
   PubMed Web of Science ®Google Scholar
• Karoulia Z, Gavathiotis E, Poulikakos PI. New perspectives for targeting RAF kinase in human cancer. Nat Rev Cancer. 2017 Nov;17(11):676–691.
   PubMed Web of Science ®Google Scholar
• Yao Z, Gao Y, Su W, et al. RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling. Nat Med. 2019;25(2):284–291.
   PubMed Web of Science ®Google Scholar
• Basile KJ, Le K, Hartsough EJ, et al. Inhibition of mutant BRAF splice variant signaling by next‐generation, selective RAF inhibitors. Pigment Cell Melanoma Res. 2014;27(3):479–484.
   PubMed Web of Science ®Google Scholar
• Peng S-B, Henry JR, Kaufman MD, et al. Inhibition of RAF isoforms and active dimers by LY3009120 leads to anti-tumor activities in RAS or BRAF mutant cancers. Cancer Cell. 2015;28(3):384–398.
   PubMed Web of Science ®Google Scholar
• Sullivan RJ, Hollebecque A, Flaherty KT, et al. A Phase I Study of LY3009120, a Pan-RAF Inhibitor, in Patients with Advanced or Metastatic Cancer. Mol Cancer Ther. 2020;19(2):460–467.
   PubMed Web of Science ®Google Scholar
• Yuan X, Tang Z, Du R, et al. RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K-RAS mutant tumors. Mol Oncol. 2020 Aug;14(8):1833–1849.
   PubMed Web of Science ®Google Scholar
• Desai J, Gan H, Barrow C, et al. Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors. J Clin Oncol. 2020;38(19):2140–2150.
   PubMed Web of Science ®Google Scholar
• Johnson DB, Lovly CM, Flavin M, et al. Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies. Cancer Immunol Res. 2015 3; Mar(3): 288–295.
   Google Scholar
• Mangana J, Cheng PF, Schindler K, et al. Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: association with Overall Survival? PLoS One. 2015;10(10):e0139438.
   PubMed Web of Science ®Google Scholar
• Clancy T, Hovig E. Profiling networks of distinct immune-cells in tumors. BMC Bioinformatics. 2016 07 04;17(1):263.
   PubMedGoogle Scholar
• Ribas A, Algazi A, Ascierto PA, et al. PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma. Nat Commun. 2020 12 07;11(1):6262.
   PubMed Web of Science ®Google Scholar
• Gogas H, Dréno B, Larkin J, et al. Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study. Ann Oncol. 2021;13(3).
   Google Scholar
• Rose AA, Armstrong SM, Hogg D, et al. Biologic subtypes of melanoma predict survival benefit of combination anti-PD1+ anti-CTLA4 immune checkpoint inhibitors versus anti-PD1 monotherapy. Journal for ImmunoTherapy of Cancer. 2021;9(1):1.
   Web of Science ®Google Scholar
• Guida M, Bartolomeo N, Quaglino P, et al. No Impact of NRAS Mutation on Features of Primary and Metastatic Melanoma or on Outcomes of Checkpoint Inhibitor Immunotherapy: an Italian Melanoma Intergroup (IMI) Study. Cancers (Basel). 2021 Jan 26;13(3):3.
   Web of Science ®Google Scholar
• Cavalcante L, Chowdhary A, Sosman JA, et al. Combining Tumor Vaccination and Oncolytic Viral Approaches with Checkpoint Inhibitors: rationale, Pre-Clinical Experience, and Current Clinical Trials in Malignant Melanoma. Am J Clin Dermatol. 2018 Oct;19(5):657–670.
   PubMed Web of Science ®Google Scholar
• Bommareddy PK, Aspromonte S, Zloza A, et al. MEK inhibition enhances oncolytic virus immunotherapy through increased tumor cell killing and T cell activation. Sci Transl Med. 2018;10(471):0417.
   Web of Science ®Google Scholar