Characterization of KRASG12C inhibitor olomorasib single-agent and combination with activity in KRASG12C-mutant models
Abstract
Abstract The impact of first-generation covalent KRAS G12C inhibitors has been reduced due to the development of drug resistance, tolerability and challenges combining with immunotherapy. We designed olomorasib, a next-generation GDP-binding KRAS G12C inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRAS G12C -mutant cancers, olomorasib reduces RAS activity and pERK levels, leading to substantial and significant tumor growth inhibition. Additionally, olomorasib combined with immune checkpoint inhibitors demonstrates greater anti-tumor activity compared to monotherapy. Furthermore, we demonstrate that olomorasib binds tightly to KRAS G12C even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRAS G12C inhibitors. These findings suggest that olomorasib could be effective for patients with KRAS G12C mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically.
Article Details
Authors (52)
Shengbin Peng
Youyan Zhang
Xi Lin
Chong Si
Robert Daniel Van Horn
Jack A. Dempsey
Eva Goetz
Robert J. Evans
Andrew Farber
Matthew J. Vandekopple
Wenyu Ming
Hong Gao
Beijing National Laboratory for Molecular Sciences (BNLMS), Institute of Chemistry
Chungping Yu
Wei Guo Xu
Nicholas E. Brown
Michele S. Dowless
Nicholas Pulliam
David A. Barda
Deqi Guo
Serge L. Boulet
Lysian Huber
Andrew Capen
Bonita Jones
Sarah Bogner
Mark A. Castanares
Jennifer Rachelle Stephens
Megan A. Johnson
Carmen L. Curtis
John M. Strelow
Junpeng Xiao
Josh Ballard
Wayne P. Bocchinfuso
Michael J. Chalmers
Jing Wang
Hunan Cancer Hospital Changsha China
Jorg Hendle
Melbert D. Saflor
Danalyn Manglicmot Lagutan
Tarun Gheyi
Anita Sarkar
Margaret Kearins
Frances Tung
Joseph Ho
Logan Rodgers
Jordi Benach
Anton Joseph Frommelt
Lian Zhou
Bradley L. Ackermann
Denis McCann
Anke Klippel
Sean G. Buchanan
James R. Henry
Xueqian Gong