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.

Automated summary

This study reveals that RGS3 enhances the GTPase activity of both mutant and wild-type KRAS proteins, leading to the inactivation of KRAS and explaining its vulnerability to emerging clinically effective therapies.