Allison Roecker

Background: Melanoma is the fifth most common cancer in the United States, and while mortality has decreased due to the approval of new immunotherapy therapies, treatment resistance remains a major hurdle to overcome.¹ Melanoma development and progression is driven by several genetic mutations, and then exacerbated by UV exposure, ultimately disrupting key signaling pathways like MAPK and Hippo.² These pathways are important for cell proliferation and survival, and their dysregulation contributes to melanoma’s aggressive and challenging nature of treatment. Understanding and targeting these pathways is essential for developing more effective, individualized therapies for better outcomes in unique melanoma tumor lines.

Objective: This review aims to explore recent research and advancements for treating melanoma. Specifically, by exploring the targeting of the MAPK and Hippo pathways in melanoma, with a focus on overcoming resistance mechanisms and improving treatment outcomes through personalized approaches.

Methods: A comprehensive literature search was conducted using PubMed, focusing on studies published between 2017 and 2025. Keywords included “melanoma,” “MAPK pathway,” “Hippo pathway,” “BRAF inhibitors,” “MEK inhibitors,” “YAP1,” “BET inhibitors,” and “anti-CD47 therapy.”

Results: Targeted therapies like BRAF and MEK inhibitors have shown promise, especially when used in combination. However, resistance often develops quickly.³ One study by Mizuno et. al tested over 100 MAPK variants and found that combining BRAF and MEK inhibitors can overcome resistance in certain variants, although some tumor mutations were still resistant.⁴ Another study by Hu R. et al showed that YAP1 expression contributes to MEK inhibitor resistance, and BET inhibitors can suppress YAP1, restoring sensitivity to treatment.¹ In addition, novel immunotherapies are being developed. A study using engineered CD47 (47E) T cells demonstrated that these modified cells can evade phagocytosis while enhancing anti-tumor immunity when combined with anti-CD47 antibodies.⁵ This dual approach allows immune cells to survive while targeting tumor cells, offering a new strategy for resistant melanomas.

Conclusion: Although melanoma treatment has advanced significantly, resistance remains a challenge. The largest goal right now in melanoma therapeutic research should be in establishing individualized approaches to the treatment of advanced melanoma, based on unique tumor modifications for better success rates in the treatment of each melanoma.

Work Cited:

1. Hu R, Hou H, Li Y, et al. Combined BET and MEK Inhibition synergistically suppresses melanoma by targeting YAP1. Theranostics. 2024;14(2):593-607. doi:10.7150/thno.85437
2. Dinter L, Karitzky PC, Schulz A, et al. BRAF and MEK inhibitor combinations induce potent molecular and immunological effects in NRAS-mutant melanoma cells: Insights into mode of action and resistance mechanisms. Int J Cancer. 2024;154(6):1057-1072. doi:10.1002/ijc.34807
3. Peiffer L, Farahpour F, Sriram A, et al. BRAF and MEK inhibition in melanoma patients enables reprogramming of tumor infiltrating lymphocytes. Cancer Immunol Immunother. 2020;70(6):1635-1647. doi:10.1007/s00262-020-02804-4
4. Mizuno S, Ikegami M, Koyama T, et al. High-Throughput Functional Evaluation of MAP2K1 Variants in Cancer. Mol Cancer Ther. 2023;22(2):227-239. doi:10.1158/1535-7163.MCT-22-0302
5. Yamada-Hunter SA, Theruvath J, McIntosh BJ, et al. Engineered CD47 protects T cells for enhanced antitumour immunity. Nature. 2024;630(8016):457-465. doi:10.1038/s41586-024-07443-8