Bcl-2 inhibition as a new therapeutic strategy to counteract melanoma progression and increase pharmacological response

Metastatic cutaneous melanoma is the deadliest form of skin cancer. Current therapies focus on the MAPK pathway and immune checkpoint inhibitors. However, treatment resistance remains a major challenge. In this scenario, the anti-apoptotic proteins Bcl-2 and Bcl-xL, belonging to the Bcl-2 family, contribute to therapy resistance and tumor progression. BH3 mimetics targeting the anti-apoptotic proteins represent a promising therapeutic opportunity in cancer. Among them, the specific Bcl-2 inhibitor, venetoclax, is currently used for the management of different hematological malignancies. Here, we demonstrated that BH3 mimetics, as single agents, reduced the viability and induced apoptosis of a panel of human melanoma cell lines. In a combinatorial regimen, they potentiated the efficacy of both target therapy and immunotherapy in preclinical melanoma models. Furthermore, our findings demonstrated that Bcl-2 regulates PD-L1 expression via the YAP/c-Myc axis. Finally, by in silico analysis, we found that patients with high Bcl-2 levels have a worse prognosis than those with low levels.