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 4

Combined eIF4A and RAS/ERK pathway inhibitors promote potent and durable responses in vivo.

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Combined eIF4A and RAS/ERK pathway inhibitors promote potent and durable...
Graphs depicting the fold change in tumor volume of (A and B) H23-derived xenograft models and (C and D) DFCI-730 PDX models treated for 28 days with vehicle, 100 mg/kg QD MRTX849 (KRASi), 0.5 mg/kg Q4D eFT226 (eIF4Ai), or the 2 agents together (Combo). Data are represented as means ± SEM. n = 7–8 tumors per condition. (B and D) Waterfall plots depicting fold change of each tumor within the 4 treatment arms after 28 days of treatment (versus day 0). ****P < 0.0001, 1-way ANOVA and Tukey’s post hoc test. Single asterisks indicate maximum tumor volume. These mice reached end point at days 21 and 25. Graphs depicting the fold change in tumor volume of (E and F) H1573-derived xenograft models and (G and H) H441-derived xenograft models treated for 28 days with vehicle, 0.6 mg/kg QD trametinib (MEKi), 0.5 mg/kg Q4D eFT226 (eIF4Ai), or the 2 agents together (Combo). Data are represented as means ± SEM. n = 7–10 tumors per condition. (F and H) Waterfall plots depicting fold change of each tumor within the 4 treatment arms after 28 days of treatment (versus day 0). ****P < 0.0001, 1-way ANOVA and Tukey’s post hoc test. Single asterisks indicate maximum tumor volume. These mice reached end point at days 18 and 21.