Targeting the MITF/APAF-1 axis as salvage therapy for MAPK inhibitors in resistant melanoma

Melanoma is a deadly form of cancer characterized by remarkable therapy resistance. Analyzing the tran-scriptome of MAPK inhibitor sensitive-and resistant-melanoma, we discovered that APAF-1 is negatively regulated by MITF in resistant tumors. This study identifies the MITF/APAF-1 axis as a molecular driver of MAPK inhibitor resistance. A drug-repositioning screen identified quinacrine and methylbenzethonium as potent activators of apoptosis in a context that mimics drug resistance mediated by APAF-1 inactivation. The compounds showed anti-tumor activity in in vitro and in vivo models, linked to suppression of MITF func-tion. Both drugs profoundly sensitize melanoma cells to MAPK inhibitors, regulating key signaling networks in melanoma, including the MITF/APAF-1 axis. Significant activity of the two compounds in inhibiting specific epigenetic modulators of MITF/APAF-1 expression, such as histone deacetylases, was observed. In sum-mary, we demonstrate that targeting the MITF/APAF-1 axis may overcome resistance and could be exploited as a potential therapeutic approach to treat resistant melanoma.

Automated summary

This study identifies the MITF/APAF-1 axis as a molecular driver of MAPK inhibitor resistance in melanoma, and quinacrine and methylbenzethonium as potent activators of apoptosis and suppressors of MITF function, demonstrating their potential as therapeutic approaches for resistant melanoma.