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.
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
Title and authors | Publication | Year |
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Small molecule modulators of B56-PP2A restore 4E-BP function to suppress eIF4E-dependent translation in cancer cells
Michelle A. Lum, Kayla A. Jonas, Shreya Parmar, Adrian R. Black, Caitlin M. O'Connor, Stephanie Dobersch, Naomi Yamamoto, Tess M Robertson, Aidan Schutter, Miranda Giambi, Rita A. Avelar, Analisa DiFeo, Nicholas T. Woods, Sita Kugel, Goutham Narla, Jennifer D. Black |
Journal of Clinical Investigation | 2025 |
lncRNAs: the unexpected link between protein synthesis and cancer adaptation
Gugnoni M, Kashyap MK, Wary KK, Ciarrocchi A |
Molecular Cancer | 2025 |
eIF4F-mediated dysregulation of mRNA translation in cancer
Amiri M, Mahmood N, Tahmasebi S, Sonenberg N |
RNA | 2025 |
Combinatorial strategies to target RAS-driven cancers.
Perurena N, Situ L, Cichowski K |
Nature reviews. Cancer | 2024 |
eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer
Boyer JA, Sharma M, Dorso MA, Mai N, Amor C, Reiter JM, Kannan R, Gadal S, Xu J, Miele M, Li Z, Chen X, Chang Q, Pareja F, Worland S, Warner D, Sperry S, Chiang GG, Thompson PA, Yang G, Ouerfelli O, de Stanchina E, Wendel HG, Rosen EY, Chandarlapaty S, Rosen N |
2024 | |
MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer
Casacuberta-Serra S, González-Larreategui Í, Capitán-Leo D, Soucek L |
Signal Transduction and Targeted Therapy | 2024 |
Artificial Intelligence Application for Anti-tumor Drug Synergy Prediction.
Peng Z, Ding Y, Zhang P, Lv X, Li Z, Zhou X, Huang S |
Current medicinal chemistry | 2024 |
eIF4A dependency: the hidden key to unlock KRAS mutant non-small cell lung cancer's vulnerability.
Casacuberta-Serra S, Gonzalez-Larreategui I, Soucek L |
Translational Lung Cancer Research | 2023 |