Inhibition of therapy-resistant and metastatic melanoma by targeting the translation initiation complex

Elevated expression of components of the translation initiation complex (eIF4F) is frequent in cancer and results in enhanced synthesis of oncogenic proteins. Given its essentiality in normal tissues, targeting eIF4F is challenging. Here, combining chemical and in silico screens, we identified a small molecule (M19 and its analog M19-6) that targets the MA3 domain of the eIF4F subunit eIF4G1, interferes with eIF4F assembly and alleviates melanoma resistance to BRAF and MEK inhibitors. Ribosome profiling revealed that the M19-6 selectively perturbs the melanoma translatome, limiting synthesis of factors that promote cell proliferation and neoplastic growth. Screens in melanoma models revealed that M19-6 synergizes with autophagy or HDAC inhibitors in cell culture and potentiates anti-neoplastic and anti-metastatic effects of doxorubicin in vivo. Overall, we describe a novel eIF4F complex inhibitor that offers a new therapeutic modality to target clinically challenging melanomas and could provide a molecular basis for combination with currently employed therapies.