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

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 6

Suppression of prosurvival proteins underlies the therapeutic response to combined eIF4A and RAS pathway inhibitors.

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Suppression of prosurvival proteins underlies the therapeutic response t...
(A) Bar graphs depicting the effects of either KRASi (left, middle) or MEKi (right) in sensitive cell lines in the presence of the indicated siRNA pools. The fold change in cell number was calculated after 72 hours of treatment (versus day 0) in response to 100 nM MRTX849 (KRASi) or 50 nM trametinib (MEKi). Data are represented as means ± SD. n = 3. The siCDK4 studies were performed separately; however, control values were similar (primary data are shown in Supplemental Figure 4). *Complete genetic ablation of MCL1 alone in H23 cells resulted in cell death, preventing further analysis. (B) Bar graphs depicting fold changes in cell numbers in cells treated for 72 hours (versus day 0) with 100 nM S63845 (MCL1i) or 1 μM navitoclax (BCL-xL/BCL-2i) or 1 μM venetoclax (BCL-2i) combined with either 100 nM MRTX849 (KRASi) or 50 nM trametinib (MEKi). Data are represented as means ± SD. n = 3. ***P < 0.001; ****P < 0.0001, 1-way ANOVA and Tukey’s post hoc test. (C) Bar graphs depicting fold change in cell number in cells treated for 72 hours with 500 nM palbociclib (CDK4/6i) combined with either 100 nM MRTX849 (KRASi) or 50 nM trametinib (MEKi). Data are represented as means ± SD. n = 3. **P < 0.01; ***P < 0.001; ****P < 0.0001, 1-way ANOVA and Tukey’s post hoc test.