Abstract 4136: The causes and consequences of off-target activation of the GCN2-eIF2a-ATF4 axis in cancer therapy

Abstract Kinase inhibitors are notorious for their promiscuity and off-target effects. We discovered that multiple clinical inhibitors used in the treatment of cancer, including dabrafenib and encorafenib, activate the GCN2 kinase at patient-relevant concentrations in an off-target manner via direct interaction. GCN2 is an activating kinase of the integrated stress response (ISR) that leads to induction of the transcription factor ATF4. Cotreatment with a GCN2 inhibitor in BRAF-V600E melanoma cells significantly alters the rate of drug resistance and cell outgrowth. We thus propose that off-target activation of GCN2 affects development of drug-resistant and metastatic phenotypes. Finally, we perform an in silico inhibitor screen, identifying dozens of FDA-approved inhibitors used in the treatment of cancer that appear to share this off-target GCN2 interaction. Citation Format: C. Ryland Ill, Nasreen Marikar, Vu Nguyen, Varuna Nangia, Alicia Darnell, Stacey Bagby, Kasey Couts, Matthew G. Vander Heiden, Philip Reigan, Sabrina L. Spencer. The causes and consequences of off-target activation of the GCN2-eIF2a-ATF4 axis in cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4136.