Notch receptors as a therapeutic target in melanoma: a narrative bibliographic review

Abstract

Melanoma is the skin cancer with higher mortality and more and more cases are arising every year. Overexpression of Notch signaling pathway elements have already been found in primary and metastatic melanoma lineages, and directly correlated to melanoma’s development, growth, angiogenesis, metastasis, and resistance to treatment. Thus, target therapy against Notch in melanoma presents a high potential for the treatment of this type of cancer. In this review we aim to perform a narrative review on melanoma’s possible treatments targeting the Notch pathway. We searched literature about Notch signaling pathway inhibitors in human cutaneous melanoma published between 2000 and 2020 using MEDLINE (via PubMed), LILACS (via Biblioteca Virtual em Saúde) and Cochrane Library databases. The selected articles were analyzed, summarized, tabulated, and used to produce the present narrative review. The 24 selected articles, as well as articles referenced in them, presented as targeting therapy against Notch, γ-secretase inhibitors (GSIs), primarily, but also gliotoxin, honokiol, phospholipase A2, andrographolide and monoclonal antibodies, that, however, were not directly studied in melanoma. Another therapy that indirectly interfered in the Notch signaling pathway and was found in these articles were G9a inhibitors. Analyzing the collected data, it was possible to conclude that GSIs, more extensively studied, are probably not the best option for melanoma’s treatment, exceeding specific scenarios or through their concomitant use with other pathways inhibitors. The use of the other compounds, on the other hand, has greater potential, however, more studies are needed to prove its effectiveness and viability for the treatment of human cutaneous melanoma.

A Review of Advanced Cutaneous Melanoma Therapies and Their Mechanisms, from Immunotherapies to Lysine Histone Methyl Transferase Inhibitors

“…In addition, G9-enhanced expression has been linked to the malignant behaviors of cancer cells such as aberrant proliferation, metastasis, and drug resistance by silencing tumor suppressors or by activating epithelia-mesenchymal transition programs [59,60]. Its overexpression is associated with different types of cancer and poor prognosis, including melanoma, due to the positive regulation of the Nocth1 signaling pathway [56,61,62]. Enhanced signaling from the Notch1 pathway specifically contributes to the development of melanoma, allowing the survival and proliferation of these cells in stressful and hypoxic environments [63][64][65][66].…”