The eIF4F complex, which is involved in the translation of RNA transcripts into proteins, selectively enhances the expression of genes that promote tumor growth and is aberrantly activated by multiple cancer-driving signaling pathways in cells. Researchers led by Ludwig Harvard’s Karen Cichowski reported in an August publication in the Journal of Clinical Investigation that an inhibitor of eIF4A, a key component of that complex, dramatically enhances the effects of KRAS inhibitors in non-small cell lung cancer (NSCLC). Activating mutations of KRAS occur in about a third of such cancers. Though drugs have been developed to target the most common KRAS mutation, G12C, they help fewer than half of NSCLC patients and only do so temporarily. Karen and her team showed the combination of eIF4A and KRAS G12C inhibitors induces significant tumor regression in mouse models of NSCLC. This cooperativity, they found, is driven by the selective translational suppression of BCL-2 family proteins, which promote cancer cell survival. Further, overexpression of the MYC oncogene, common in cancer, confers sensitivity to the combination because it creates a dependency on eIF4A for expression of BCL-2 family proteins. The researchers also showed that eIF4A inhibition similarly cooperates with MEK inhibitors, suggesting an alternative strategy to treat lung cancers that harbor other kinds of activating KRAS mutations.
Cotargeting a MYC/eIF4A-survival axis improves the efficacy of KRAS inhibitors in lung cancer
Journal of Clinical Investigation, 2023 August 15