Melanoma: Aberrant Signaling Pathways and Therapeutic Approaches

There are three major types of skin cancer: basal cell carcinoma, squamous cell carcinoma, and melanoma. Melanomas are the most lethal of the three, accounting for 90% of skin cancer deaths. When found early, the 5-year survival rate for localized melanoma is 99%. However, this number significantly decreases to 63% and 20% for melanoma with regional and distant metastasis, respectively. A big contributor to this poor prognosis is the lack of effective, durable treatments for unresectable, metastatic melanoma.^1,2

Melanomas exhibit a high rate of somatic mutations compared to other types of cancer. The majority of these mutations are passenger, or silent, mutations that are not vital for melanoma development. However, numerous mutations have been identified as oncogenic, or "driver," mutations that result in constitutive activation of signaling pathways that promote tumor growth and survival.³

Melanoma-Promoting Oncogenic Mutations in the MAPK and PI3K/Akt Pathways

MAPK Signaling in Melanoma

B-Raf is the most frequently mutated oncogene in melanoma, with the B-Raf^V600E mutation being the most prevalent mutation, occurring in over 50% of cases. The mutation drives sustained proliferative signaling in skin cells. N-Ras, the second most common mutation, is found in approximately 30% of all melanomas. Both of these mutations lead to subsequent activation of MEK downstream, which in turn activates MAPK.

Mutations in other oncogenes, such as c-Kit and Gαq, also protomte the MAPK pathway by activating key proteins like Ras, Raf, MEK, and MAPK. Collectively, aberrant activation of the MAPK pathway is found in over 90% of melanoma, making it an ideal target for therapeutic intervention.^1,4 Several inhibitors targeting B-Raf and MEK have been approved by the FDA for the treatment of melanoma.

P13K/AKT Signaling in Melanoma

The PI3K/Akt pathway, which regulates cell proliferation and survival, is also implicated in melanoma. Interestingly, Ras sits at the intersection between the MAPK and PI3K pathways. Thus, Ras protein mutations can activate both pathways. High levels of phosphorylated Akt have been observed in two-thirds of primary and metastatic melanomas. This may partially be due to loss of function mutations in PTEN observed in 10-30% of melanomas. mTOR mutations are also present in 10% of melanomas and correlate with poorer survival statistics.^1,3

Additional Potential Therapeutic Targets for Melanoma

Other pathways with potential therapeutic targets include the Wnt and NF-kB pathways. However, targeted therapies against a known oncogenic driver are effective at first, but don’t typically last once the tumor acquires resistance. Thus, new strategic approaches are needed to improve clinical outcomes for patients. One option is to target multiple drivers at once. For example, studies have shown better outcomes when patients are treated with a B-Raf inhibitor with a MEK inhibitor. Another approach is to understand mechanisms of chemotherapy resistance to identify ways to extend the efficacy of the targeted therapeutic. Some mechanisms currently under investigation are the reactivation of the MAPK pathway through, for example, the selective amplification of B-Raf^V600E mutations or activation of alternative oncogenic pathways like the upregulation of PDGFRβ, c-Met, or IGF-1R.³

Harnessing the Immune System: Immunotherapeutic Approaches for Melanoma Researchers

Another potential approach is to combine a targeted therapy with an immunotherapy like pembrolizumab, nivolumab, or ipilimumab that target checkpoint inhibitors like PD-1/PD-L1or CTLA-4. Long-term remission for advanced melanomas has been achieved with immunotherapies, but the response rate is low. Identifying a treatment strategy that combines the response rate of a targeted therapeutic with the durability of an immunotherapy would be ideal. However, finding the exact combination has been elusive to date. Clinical trials investigating treating patients with a B-Raf inhibitor and anti-CTLA-4 immunotherapy were initially promising but ultimately halted when hepatotoxicity, gastrointestinal toxicity, and skin adverse events occurred. Finding the right treatment combination, sequence, and timing will help maximize efficacy and durability while improving survival rates for those with metastatic melanoma. Gaining a better understanding of the interplay between different targeted therapies and immunotherapies will enable the design of combinatorial regimens to eliminate metastatic melanoma.²

Select References

1. Teixido C, Castillo P, Martinez-Vila C, Arance A, Alos L. Molecular Markers and Targets in Melanoma. Cells. 2021; 10(9):2320. doi: 10.3390/cells10092320.
2. Yu C, Liu X, Yang J, Zhang M, Jin H, Ma X, Shi H. Combination of Immunotherapy With Targeted Therapy: Theory and Practice in Metastatic Melanoma. Front Immunol. 2019 May 7;10:990. doi: 10.3389/fimmu.2019.00990.
3. Khaddour K, Maahs L, Avila-Rodriguez AM, Maamar Y, Samaan S, Ansstas G. Melanoma Targeted Therapies beyond BRAF-Mutant Melanoma: Potential Druggable Mutations and Novel Treatment Approaches. Cancers (Basel). 2021 Nov 22;13(22):584.
4. Wellbrock C, Arozarena I. The Complexity of the ERK/MAP-Kinase Pathway and the Treatment of Melanoma Skin Cancer. Front Cell Dev Biol. 2016 Apr 27;4:33. doi: 10.3389/fcell.2016.00033.