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There is a lack of appropriate melanoma models that can be used to evaluate the efficacy of novel therapeutic modalities. Here, we discuss the current state of the art of melanoma models including genetically engineered mouse, patient-derived xenograft, zebrafish, and ex vivo and in vitro models. We also identify five major challenges that can be addressed using such models, including metastasis and tumor dormancy, drug resistance, the melanoma immune response, and the impact of aging and environmental exposures on melanoma progression and drug resistance. Additionally, we discuss the opportunity for building models for rare subtypes of melanomas, which represent an unmet critical need. Finally, we identify key recommendations for melanoma models that may improve accuracy of preclinical testing and predict efficacy in clinical trials, to help usher in the next generation of melanoma therapies., Competing Interests: Declaration of interests D.J.A. is a paid consultant for Microbiotica and receives grant support from AstraZeneca and OpenTargets. N.A. is a consultant for Viela Bio. A.E.A. reports receiving a commercial research grant from Pfizer. (2013–2017) and has ownership interest in patent number 9880150. M.B. is a consultant for Eli Lilly and Company and Bristol-Myers Squibb. P.C. received grants and personal fees from Deciphera, personal fees from Exelixis, grants from Array/Pfizer, and personal fees from Zai lab. S. Khan has a US patent pending (62/654,025). S. Kobold received research support from TCR2 Inc and Arcus Bioscience for work unrelated to this manuscript, has licensed IP to TCR2 Inc, has received consultancy fees from TCR2 Inc and Novartis, and is an inventor of several patents and patent applications in the field of cancer immunotherapy. R.M. consults for Pfizer, and as a former employee of the Institute of Cancer Research he may benefit financially from drug-discovery programs that are commercialized. M.M. receives research funding from Pfizer and Deciphera Pharma; serves as a scientific advisor to Pfizer, Deciphera Pharma, Revolution Medicine, and ARO; and receives royalty income from the University of California for Braf(CA) mice, which are the basis of several GEM models of BRAF(V600E)-driven melanoma described in this review. Z.A.R. is founder and scientific advisor of Pangea Therapeutics. Y.S. is a consultant of Achilles Therapeutics Limited. A.T.W. sits on the advisory board for Melanoma Research Foundation, Phoremost Technologies, and Healthe Scientific. R.M.W. is a paid consultant to N-of-One Therapeutics, a subsidiary of Qiagen; is on the Scientific Advisory Board of Consano but receives no income for this; and receives royalty payments for the use of the casper line from Carolina Biologicals. L.I.Z. is a founder and stockholder of Fate Therapeutics, CAMP4 Therapeutics, and Scholar Rock, and a consultant for Celularity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Oncogene-induced senescence, e.g., in melanocytic nevi, terminates the expansion of pre-malignant cells via transcriptional silencing of proliferation-related genes due to decoration of their promoters with repressive trimethylated histone H3 lysine 9 (H3K9) marks. We show here that structurally distinct H3K9-active demethylases-the lysine-specific demethylase-1 (LSD1) and several Jumonji C domain-containing moieties (such as JMJD2C)-disable senescence and permit Ras/Braf-evoked transformation. In mouse and zebrafish models, enforced LSD1 or JMJD2C expression promoted Braf-V600E-driven melanomagenesis. A large subset of established melanoma cell lines and primary human melanoma samples presented with a collective upregulation of related and unrelated H3K9 demethylase activities, whose targeted inhibition restored senescence, even in Braf inhibitor-resistant melanomas, evoked secondary immune effects and controlled tumor growth in vivo., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Heterozygous mutation of IDH1 in cancers modifies IDH1 enzymatic activity, reprogramming metabolite flux and markedly elevating 2-hydroxyglutarate (2-HG). Here, we found that 2-HG depletion did not inhibit growth of several IDH1 mutant solid cancer types. To identify other metabolic therapeutic targets, we systematically profiled metabolites in endogenous IDH1 mutant cancer cells after mutant IDH1 inhibition and discovered a profound vulnerability to depletion of the coenzyme NAD+. Mutant IDH1 lowered NAD+ levels by downregulating the NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (Naprt1), sensitizing to NAD+ depletion via concomitant nicotinamide phosphoribosyltransferase (NAMPT) inhibition. NAD+ depletion activated the intracellular energy sensor AMPK, triggered autophagy, and resulted in cytotoxicity. Thus, we identify NAD+ depletion as a metabolic susceptibility of IDH1 mutant cancers., (Copyright © 2015 Elsevier Inc. All rights reserved.)

PIK3CA is mutated in diverse human cancers, but the functional effects of these mutations have not been defined. To evaluate the consequences of PIK3CA alterations, the two most common mutations were inactivated by gene targeting in colorectal cancer (CRC) cells. Biochemical analyses of these cells showed that mutant PIK3CA selectively regulated the phosphorylation of AKT and the forkhead transcription factors FKHR and FKHRL1. PIK3CA mutations had little effect on growth under standard conditions, but reduced cellular dependence on growth factors. PIK3CA mutations resulted in attenuation of apoptosis and facilitated tumor invasion. Treatment with the PI3K inhibitor LY294002 abrogated PIK3CA signaling and preferentially inhibited growth of PIK3CA mutant cells. These data have important implications for therapy of cancers harboring PIK3CA alterations.