Oncogenic mutant KRAS inhibition through oxidation at Cysteine 118

Specific reactive oxygen species (ROS) activate KRAS by reacting with Cysteine 118 (C118). Here we have mimicked a permanent oxidation of human KRAS at C118 by replacing Cysteine 118 with Aspartic acid (C118D) in KRAS to show that mutant KRAS is selectively inhibited via oxidation at C118, both in vitro and in vivo. Moreover, the combined treatment of hydrogen peroxide producing pro-oxidant Paraquat and nitric oxide producing inhibitor L-NAME selectively inhibits human mutant KRAS activity by inducing oxidization at C118. Our study shows for the first time the vulnerability of human mutant KRAS to oxidation, thereby paving the way to explore oxidation based anti-KRAS treatments in humans.