Translation initiation factor 2B (eIF2B) stimulates mutant KRAS function in cancer

Abstract KRAS mutations appear with high frequency in colorectal, lung and pancreatic cancers, which are the three leading causes of new cancer deaths worldwide. Mutant KRAS is preferentially bound to GTP resulting in continuous cell proliferation. Mutant KRAS exposes cells to oncogenic forms of stress (i.e. genotoxic, metabolic, proteostatic stress), which disrupt proliferation and tissue homeostasis. To cope with stress, cells engage pro-adaptive mechanisms, which act in favor of mutant KRAS to transform cells. An important adaptation mechanism to stress acts at the level of mRNA translation and involves the functional interplay between the translation initiator factors eIF2 and eIF2B. Phosphorylated eIF2 mediates a translational and transcriptional reprogramming to promote adaptation under stress, a process that is antagonized by the guanine exchange function (GEF) of eIF2B. We demonstrate the physical interaction between mutant KRAS and eIF2B by mass spectrometry. Using genetic approaches, we show that eIF2B is required for the survival and proliferation of tumor cells with KRAS mutations via the stimulation of MAPK signaling. We also show that eIF2B contributes to increased resistance of tumor cells to pharmacological inhibition of mutant KRAS forms. Genetic inactivation of eIF2B promotes the formation of mutant KRAS-GDP complexes whereas its pharmacological stimulation facilitates mutant KRAS-GTP complex formation in tumor cells; this data supports a potential GEF function for eIF2B towards mutant KRAS. Cell imaging experiments provide strong evidence for the implication of eIF2B in the association of mutant KRAS with the plasma membrane of tumor cells. Our findings reveal a stimulatory role of eIF2B in mutant KRAS signaling and provide a previously unidentified link between mutant KRAS and mRNA translation with implications in the growth and treatment of cancers with KRAS mutations. Citation Format: Hyungdong Kim, Nour Ghaddar, Laleh Ebrahimi Ghahnavieh, Shuo Wang, Kwang-Jin Cho, Atsuo Sasaki, Antonis E. Koromilas. Translation initiation factor 2B (eIF2B) stimulates mutant KRAS function in cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A022.