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

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 1

eIF4A inhibitors dramatically sensitize NSCLCs to KRAS G12C inhibitors.

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eIF4A inhibitors dramatically sensitize NSCLCs to KRAS G12C inhibitors. ...
(A) Bar graph depicting the fold change in cell numbers after 72 hours (versus day 0) using a panel of KRAS G12C–mutant NSCLC cells grown in 3D conditions. Cells were treated with vehicle (DMSO), 25 nM eFT226 (eIF4Ai), 100 nM MRTX849 (KRASi), or both agents together (Combo). Data are represented as mean ± SD. n = 3. ***P < 0.001; ****P < 0.0001, 1-way ANOVA and Tukey’s post hoc test. (B) Representative photographs of sensitive KRAS G12C–mutant NSCLC spheroids after 72 hours of indicated drug treatments. Images were obtained using the 2X Bright Field channel. Original magnification, ×2. (C) Bar graph depicting fold change in cell numbers after 72 hours (versus day 0) in the same panel of cell lines grown in 2D tissue-culture conditions with 2% serum. Cells were treated with vehicle (DMSO), 25 nM eFT226 (eIF4Ai), 100 nM MRTX849 (KRASi), or both agents together (Combo). Data are represented as means ± SD. n = 3. ****P < 0.0001, 1-way ANOVA and Tukey’s post hoc test). (D) Immunoblots showing suppression of phospho-ERK by MRTX849 (KRASi, 100 nM) and/or eFT226 (eIF4Ai, 25 nM) after 24 hours of treatment. (E) Bar graphs depicting fold change in cell number of specified cell lines transfected with either siCNT or siEIF4A1 and treated with vehicle (DMSO) or 100 nM MRTX849 (KRASi) for 72 hours in 2D/low-serum conditions. Data are represented as means ± SD. n = 3. ****P < 0.0001, 1-way ANOVA and Tukey’s post hoc test. Immunoblots confirm suppression of eIF4A1 by siRNAs.