Melanoma: From Molecular Mechanisms to Therapeutic Opportunities—3rd Edition

Dear Colleagues,

In March 2022, our Special Issue "Melanoma: From Molecular Mechanisms to Therapeutic Opportunities" was launched (https://www.mdpi.com/journal/cells/special_issues/Melanoma_Molecular_Mechanism). Then, in June 2023, we published a second edition of this Special Issue (https://www.mdpi.com/journal/jcm/special_issues/EN152GA579).

Malignant melanoma remains a formidable challenge, with ~106,110 new cases and ~7180 deaths in the United States in 2021. Drug and immune resistance, together with invasion and metastasis, determine tumor progression, and, ultimately, patient survival. With the highest mortality rate among skin cancers, cutaneous melanoma is associated with driver mutations in MAPK and other signaling pathways, including RAS/PI3K/AKT, p16INK4a/CDK4/RB, WNT, and p53. Activating mutations are primarily found in the V600 or K601 of BRAF (50% of melanomas), Q61 of NRAS (>20%), and LOF mutations in NF1 (10%). Although combinations of targeted kinase inhibitors for BRAF and MEK, combined with immune checkpoint inhibitors, have improved progression-free and overall survival in melanoma patients, ~75% of melanomas recur after BRAF copy number gains, alternative splicing, MEK1/2, and NRAS gain-of-function mutations; 20% of BRAFi-resistant melanomas upregulate compensatory PI3K/AKT survival pathways. Although treatment for recalcitrant NRAS-mutant metastatic tumors has advanced, with immunotherapies anti–PD-1, anti-PD-L1, and/or anti-CTLA4 proving efficacious, many patients remain unresponsive, and chemotherapy with dacarbazine, temozolomide, or carboplatin shows limited success. There is a compelling rationale to examine unexploited pathways. Resistance has been attributed to subpopulations of “melanoma initiating cells”, highly tumorigenic cancer stem cells characterized by melanosphere formation, and the expression of specific cancer stem cell markers.

This Special Issue will publish original articles and reviews focusing on novel targets for therapeutic intervention; biomarkers for use in screening, predicting treatment response, and monitoring disease progression; and mechanistic insights and advances in molecular and cellular pathways involved in melanomagenesis and progression. Topics of interest include the mechanisms underlying melanoma progression and treatment response, signal transduction, melanoma-initiating cells, drug resistance, invasiveness, immune evasion, and metastasis. There is still an urgent need to identify novel targets and develop new combinatorial therapeutic approaches that can overcome drug resistance mechanisms.

Due to the success of the first two editions, we have decided to move forward with launching the third edition, with the aim of showcasing a range of original works. We are very keen to attract a global audience, and we welcome contributions on this subject from around the world, including both solicited and unsolicited submissions.

Prof. Dr. Cynthia Simbulan-Rosenthal
Dr. Dean S. Rosenthal
Guest Editors

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