Abstract
Simple SummaryAdvances in melanoma treatment include v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors that target the predominant oncogenic mutation found in malignant melanoma. Despite initial success of the BRAF inhibitor (BRAFi) therapies, resistance and secondary cancer often occur. Mechanisms of resistance and secondary cancer rely on upregulation of pro-survival pathways that circumvent senescence. The repeated identification of a cellular senescent phenotype throughout melanoma progression demonstrates the contribution of senescent cells in resistance and secondary cancer development. Incorporating senotherapeutics in melanoma treatment may offer a novel approach for potentially improving clinical outcome.BRAF is the most common gene mutated in malignant melanoma, and predominately it is a missense mutation of codon 600 in the kinase domain. This oncogenic BRAF missense mutation results in constitutive activation of the mitogen-activate protein kinase (MAPK) pro-survival pathway. Several BRAF inhibitors (BRAFi) have been developed to specifically inhibit BRAFV600 mutations that improve melanoma survival, but resistance and secondary cancer often occur. Causal mechanisms of BRAFi-induced secondary cancer and resistance have been identified through upregulation of MAPK and alternate pro-survival pathways. In addition, overriding of cellular senescence is observed throughout the progression of disease from benign nevi to malignant melanoma. In this review, we discuss melanoma BRAF mutations, the genetic mechanism of BRAFi resistance, and the evidence supporting the role of senescent cells in melanoma disease progression, drug resistance and secondary cancer. We further highlight the potential benefit of targeting senescent cells with senotherapeutics as adjuvant therapy in combating melanoma.
Highlights
Introduction published maps and institutional affilMelanoma is a cancer originating from melanocytes, the pigment producing cells in the skin [1]
We explore the specific BRAFV600E mutation and discuss additional gene mutations often found in conjunction with BRAF mutations that lead to melanoma
Several targeted therapies have been developed toward oncogenic BRAF in malignant melanoma that significantly improve progression free survival (PFS), but resistance often develops
Summary
The use of MEK inhibitors (MEKi) in combination with BRAFi was to prevent the paradoxical and reactivation of the MAPK pathway that leads to resistance and cSCC development [58,93,100,101]. The addition of MEKi were successful in reducing the incidence of cSCC and increasing PFS, but resistance routinely still develops. The combination treatments are Vemurafenib with Cobimetinib [102], Dabrafenib with Trametinib [103], and Encorafenib with Binimetinib [57]. While the MEK inhibitors reduce secondary cSCC, the two drugs target the same molecular pathway, increasing the chances of resistance and secondary cancer to occur through alternative pathways (Figure 2)
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