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.

Oxidative-Stress-Sensitive microRNAs in UV-Promoted Development of Melanoma

“…Of note, the mutation frequency rate in melanoma is higher than that described for most other cancers. In this context, strong evidence indicates that UV-induced DNA lesions represent a major causative factor for mutations in melanoma-relevant genes [8][9][10][11][12]. Typical and atypical UV mutation signatures can be related to the direct absorption of UV energy with the formation of secondary photoproducts, as well as consequent to UV-generated ROS able to oxidize nucleotide bases [38][39][40][41][42].…”

“…Several signaling pathways have been associated with abnormal proliferation, growth, survival, migratory, and invasive properties of neoplastic melanocytes. In particular, among the underlying molecular aberrations characterizing melanoma and its etiology, the most frequent molecular changes involve genetic mutations of CDKN2A, CCND1, CDK4, MITF, c-KIT and MC1R genes; dysregulation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-Akt pathways; aberrant p53, STAT3, NRF2, NFκB, cadherin, and Wnt signaling pathways; and epigenetic alterations [8][9][10][11][12]. Ultimately, a complex and intricate connection between these aberrant signaling pathways and genetic abnormalities leads to a cascade of molecular events promoting uncontrolled melanocyte growth, proliferation, differentiation, migration and greater cell survival, resistance to apoptosis, invasion, and metastasis, which collectively promote tumorigenesis [8][9][10][11][12].…”

Changes in the Transcriptome and Chromatin Landscape in BRAFi-Resistant Melanoma Cells

“…However, acquired resistance to these agents remains a major hurdle preventing the success of targeted therapies and limiting their benefits. One approach to overcoming this limitation is to understand the mechanisms underlying acquired resistance (40)(41)(42), which can contribute to modifying therapeutic regimens or developing combination therapies to prevent the emergence of drug resistance.…”

Functionalization of Nanomaterials for Skin Cancer Theranostics

“…To overcome the therapeutic resistance, inhibition of pathways mentioned above is attempted in clinical trials ( Nathanson et al, 2013 ; Sullivan and Flaherty, 2015 ; Romano et al, 2018 ; Sullivan et al, 2018 ). Nevertheless, inhibition of cyclin dependent kinase4/6 (CDK4/6) and MEK is further limited by adverse effects that need a lower dose, leading to diminished effectiveness and susceptibility to resistance development ( Kwong et al, 2012 ; Guo et al, 2021 ).…”