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Cotargeting a MYC/eIF4A-survival axis improves the efficacy of KRAS inhibitors in lung cancer
Francesca Nardi, … , Pasi A. Jänne, Karen Cichowski
Francesca Nardi, … , Pasi A. Jänne, Karen Cichowski
Published June 29, 2023
Citation Information: J Clin Invest. 2023;133(16):e167651. https://doi.org/10.1172/JCI167651.
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Research Article Oncology

Cotargeting a MYC/eIF4A-survival axis improves the efficacy of KRAS inhibitors in lung cancer

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Abstract

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 cotarget 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 identifying the most therapeutically important eukaryotic initiation factor 4F complex–translated (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.

Authors

Francesca Nardi, Naiara Perurena, Amy E. Schade, Ze-Hua Li, Kenneth Ngo, Elena V. Ivanova, Aisha Saldanha, Chendi Li, Prafulla C. Gokhale, Aaron N. Hata, David A. Barbie, Cloud P. Paweletz, Pasi A. Jänne, Karen Cichowski

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Figure 9

MYC overexpression creates a dependency on eIF4A for the expression of prosurvival proteins.

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MYC overexpression creates a dependency on eIF4A for the expression of p...
(A) Immunoblots showing MCL1, BCL-xL, and BCL-2 protein levels in response to 24 hours of specified treatments in control and MYC-overexpressing resistant lines. (B and C) Immunoblots showing interactions of MCL1 and BCL-xL with immunoprecipitated proapoptotic BIM and BAX proteins, respectively, in response to specified drug treatments in control and MYC-overexpressing resistant lines. The GAPDH immunoblots denoted by asterisks, which serve as a loading control, have been duplicated from the left side of that panel, because immunoblots were all generated from the same gel and membrane. (Right) Immunoblots confirm ectopic expression of MYC by cDNAs.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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