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

• Published in: The Journal of clinical investigation Vol. 133; no. 16; pp. 1 - 16
• Main Authors: Nardi, Francesca, Perurena, Naiara, Schade, Amy E., Li, Ze-Hua, Ngo, Kenneth, Ivanova, Elena V., Saldanha, Aisha, Li, Chendi, Gokhale, Prafulla C., Hata, Aaron N., Barbie, David A., Paweletz, Cloud P., Jänne, Pasi A., Cichowski, Karen
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.08.2023
• Subjects: Ablation; Apoptosis; Bcl-2 protein; Bcl-x protein; Biomarkers; Biomedical research; Biotechnology industry; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; Cells; Clinical trials; Cooperation; Cytotoxicity; Drug therapy; Eukaryotic Initiation Factor-4F - metabolism; Gene expression; Genetic aspects; Health aspects; Humans; K-Ras protein; Kinases; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Mcl-1 protein; Molecular targeted therapy; Mutation; Myc protein; Non-small cell lung carcinoma; Oncology; Oncology, Experimental; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Small cell lung carcinoma; TOR protein; TOR Serine-Threonine Kinases - metabolism; Toxicity; Transcription factors; Tumors; United States; Massachusetts; Signal transduction; Oncology; Drug therapy; Lung cancer
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI167651

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.