HYPER-ACTIVATION OF MUTANT KRAS DRIVES REDOX-DEPENDENT CELL DEATH INVOLVING MTORC2/AKT SIGNALING AND MITOCHONDRIAL MORPHOLOGY CHANGES

Abstract

RAS is one of the most commonly mutated oncogenes in cancer. Interestingly, many studies have implicated oncogenic RAS in the production of reactive oxygen species (ROS), which serve as important signaling molecules during RAS-induced transformation. The dependency on ROS for transformation simultaneously confers vulnerability of RAS-driven cancers towards oxidative-stress induced cell death. This study uncovered a novel cell death mechanism wherein drug-induced hyper-activation of mutant KRAS, drives AKT-dependent ROS production, inducing cell death. Notably, full activation of AKT by rictor-dependent mammalian target of rapamycin complex 2 (mTORC2) is critical for the ROS-producing activity of AKT in this model. Hyper-activation of KRAS also induces mitochondrial fragmentation downstream of KRAS which is partially involved in cell death. These findings demonstrated a novel approach in targeting KRAS-driven cancer through paradoxical activation of KRAS, leveraging on its ROS producing activity through AKT to drive cells towards redox-catastrophe.