The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS

Recently reported to be effective in patients with lung cancer, KRAS(G12C) inhibitors bind to the inactive, or guanosine diphosphate (GDP)-bound, state of the oncoprotein and require guanosine triphosphate (GTP) hydrolysis for inhibition. However, KRAS mutations prevent the catalytic arginine of GTPase-activating proteins (GAPs) from enhancing an otherwise slow hydrolysis rate. If KRAS mutants are indeed insensitive to GAPs, it is unclear how KRAS(G12C) hydrolyzes sufficient GTP to allow inactive state-selective inhibition. Here, we show that RGS3, a GAP previously known for regulating G protein-coupled receptors, can also enhance the GTPase activity of mutant and wild-type KRAS proteins. Our study reveals an unexpected mechanism that inactivates KRAS and explains the vulnerability to emerging clinically effective therapeutics.