黑色素瘤：异常信号转导通路和治疗方法

皮肤癌有三种主要类型：基底细胞癌、鳞状细胞癌和黑色素瘤。黑色素瘤是三者中最致命的，占皮肤癌死亡例数的 90%。早期发现时，局限化黑色素瘤的 5 年生存率为 99%。然而，对于发生区域和远端转移的黑色素瘤，这个数值分别显著降至 63% 和 20%。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. 这些突变中大多数者是对黑色素瘤形成并不重要的过客突变或沉默突变。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

MAPK 通路和 PI3K/Akt 通路中促黑色素瘤的致瘤性突变

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

黑色素瘤的其他潜在治疗靶

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

利用免疫系统：黑色素瘤研究人员的免疫治疗方法

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

选择以下参考文献

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 2020.05.7;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 2020.11.22;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.