Signal pathways of melanoma and targeted therapy

Abstract

Melanoma is the most lethal skin cancer that originates from the malignant transformation of melanocytes. Although melanoma has long been regarded as a cancerous malignancy with few therapeutic options, increased biological understanding and unprecedented innovations in therapies targeting mutated driver genes and immune checkpoints have substantially improved the prognosis of patients. However, the low response rate and inevitable occurrence of resistance to currently available targeted therapies have posed the obstacle in the path of melanoma management to obtain further amelioration. Therefore, it is necessary to understand the mechanisms underlying melanoma pathogenesis more comprehensively, which might lead to more substantial progress in therapeutic approaches and expand clinical options for melanoma therapy. In this review, we firstly make a brief introduction to melanoma epidemiology, clinical subtypes, risk factors, and current therapies. Then, the signal pathways orchestrating melanoma pathogenesis, including genetic mutations, key transcriptional regulators, epigenetic dysregulations, metabolic reprogramming, crucial metastasis-related signals, tumor-promoting inflammatory pathways, and pro-angiogenic factors, have been systemically reviewed and discussed. Subsequently, we outline current progresses in therapies targeting mutated driver genes and immune checkpoints, as well as the mechanisms underlying the treatment resistance. Finally, the prospects and challenges in the development of melanoma therapy, especially immunotherapy and related ongoing clinical trials, are summarized and discussed.

Fig. 1

Clinical and corresponding histopathological images of melanomas. Generally, melanomas are classified into four main types according to the histopathological characteristics, namely, superficial spreading melanoma (a), nodular melanoma (b), lentigo maligna melanoma (c), and acral lentiginous melanoma (d). The corresponding histopathological image of the same patient is displayed on the right. Scale bar = 100 μm

Fig. 2

Timeline for FDA-approved therapies for metastatic melanoma. HD high-dose, Ipi Ipilimumab, T-VEC talimogene laherparepvec

Fig. 3

Mutated driver genes and downstream signal pathways in melanoma. Ampl amplification, CDK cyclin-dependent kinase, Del deletion, GPCR G protein-coupled receptor, Mut mutation, P (in a pink circle) phosphate, p14^ARF and p16^INK4A splice variant encoded by CDKN2A gene, PIP2 phosphatidylinositol-(4,5)-bisphosphate, PIP3 phosphatidylinositol-(3,4,5)-trisphosphate, PTEN phosphatidylinositol‑3,4,5‑trisphosphate 3‑phosphatase, and dual-specificity protein phosphatase, RB retinoblastoma-associated protein, RTK receptor tyrosine kinase, SCF stem cell factor

Fig. 4

Key transcriptional factors and signal pathways in melanoma. ADAM10 ADAM metallopeptidase domain 10, APC adenomatosis polyposis coli, DLL delta-like canonical Notch ligand, DVL Disheveled segment polarity protein, FZD frizzled class receptor, GSK3β Glycogen synthase kinase 3β, JAG jagged canonical Notch ligand, LEF-1 lymphoid enhancer binding factor 1, LRP5/6 low density lipoprotein receptor-related protein 5/6, MAML mastermind-like transcriptional coactivator, NICD Notch intracellular domain, P/CAF P300/CBP-associated factor, RBPJ recombination signal binding protein for immunoglobulin κ J region, TACE TNFα-converting enzyme

Fig. 5

Epigenetic regulation in melanoma. Main paradigms of epigenetic modification and representative effects on cancer biology in melanoma

Fig. 6

Signal pathways of metabolic reprogramming in melanoma. AA acetoacetate, ACLY ATP-citrate lyase, BCAT branched-chain amino acid transaminase, BCKA branched-chain keto acids, FA fatty acid, FASN fatty acid synthase, GLS glutaminase, GLUT1 glucose transporter type 1, GOT1 glutamicoxaloacetic transaminase 1, HK1/2 hexokinase 1/2, HMGCL 3-hydroxy-3-methylglutaryl-CoA lyase, HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase, LDHA lactate dehydrogenase A, MCT1/4 monocarboxylate transporter, MVA mevalonate, MVK mevalonate kinase, OAA oxaloacetate, PDH pyruvate dehydrogenase, PFK1/2 phosphofructokinase 1/2, PKM2 pyruvate kinase M, SREBP-1 sterol regulatory element-binding transcription factor 1, TFEB transcription factor EB