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Melanoma is a deadly form of cancer characterized by high aggressiveness and remarkable therapy-resistance. The inactivation of apoptosis constitutes a common strategy adopted by cancer cells to survive death-stimulating drugs. We examined the transcriptome of human melanoma samples responders and resistant to MAPK inhibitors and discovered that APAF-1, the main component of apoptosome, is downregulated in resistant tumors. The decreased expression of APAF-1 was correlated with high levels of the melanoma survival oncogene MITF . We therefore demonstrated that the MITF/APAF-1 axis could be relevant in driving resistance to MAPK inhibitor treatments. 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. Our findings demonstrated the pro-apoptotic and tumor-suppressor activity of the compounds in a large panel of melanoma cells, including patient-derived cells and in vivo models, where the two drugs showed remarkable suppression of MITF function. Quinacrine and Methylbenzethonium profoundly sensitize BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors, thus indicating their pharmacological relevance in melanoma. Transcriptomic profiles of melanoma cells revealed that both compounds regulate key-signaling networks in melanoma, including the MITF gene network. In summary, we demonstrate that inhibiting a driver of MAPK inhibitor resistance could improve current approaches of targeted melanoma therapy.