Co-targeting a MYC-eIF4A survival axis improves the efficacy of KRAS inhibitors in lung cancer

Despite the success of KRAS G12C inhibitors in non-small cell lung Cancer (NSCLC), more effective treatments are needed. One preclinical strategy has been to co-target Ras and mTOR pathways, however toxicity due to broad mTOR inhibition has limited its utility. Therefore, we sought to develop a more refined means of targeting cap-dependent translation and identify the most therapeutically important eIF4F-translated targets. Here we show that an eIF4A inhibitor, which targets a component of eIF4F, dramatically enhances the effects of KRAS G12C inhibitors in NSCLCs and together these agents induce potent tumor regression in vivo. By screening a broad panel of eIF4F targets, we show that this cooperativity is driven by effects on Bcl-2 Family proteins. Moreover, because multiple Bcl-2 Family members are concomitantly suppressed, these agents are broadly efficacious in NSCLCs, irrespective of their dependency on MCL1, Bcl-xL, or Bcl-2, which is known to be heterogeneous. Finally, we show that MYC overexpression confers sensitivity to this combination because it creates a dependency on eIF4A for Bcl-2 Family protein expression. Together, these studies identify a promising therapeutic strategy for KRAS-mutant NSCLCs, demonstrate that Bcl-2 proteins are the key mediators of the therapeutic response in this tumor type, and uncover a predictive biomarker of sensitivity.