Journal Article

Characterization of KRAS G12C inhibitor olomorasib single-agent and combination with activity in KRAS G12C -mutant models

Si, Chong, Curtis, Carmen L, Gheyi, Tarun, Bogner, Sarah, Peng, Shengbin, Barda, David A, Gao, Hong, Dempsey, Jack A, Buchanan, Sean G, Tung, Frances, Goetz, Eva, Boulet, Serge L, Kearins, Margaret, Jones, Bonita, Ho, Joseph, Strelow, John M, Farber, Andrew, Castanares, Mark A, Johnson, Megan A, Saflor, Melbert D, Benach, Jordi, Rodgers, Logan, Gong, Xueqian, Brown, Nicholas E, Stephens, Jennifer Rachelle, Evans, Robert J, Ming, Wenyu, Zhou, Lian, Henry, James R, Xu, Wei Guo, Hendle, Jorg, Bocchinfuso, Wayne P, Ackermann, Bradley L, Dowless, Michele S, Chalmers, Michael J, Lin, Xi, Sarkar, Anita, McCann, Denis, Vandekopple, Matthew J, Yu, Chungping, Klippel, Anke, Wang, Jing, Zhang, Youyan, Ballard, Josh, Van Horn, Robert Daniel, Pulliam, Nicholas, Capen, Andrew, Huber, Lysian, Lagutan, Danalyn Manglicmot, Frommelt, Anton Joseph, Xiao, Junpeng, Guo, Deqi

2026

Overview

The impact of first-generation covalent KRAS 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 inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRAS -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 even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRAS inhibitors. These findings suggest that olomorasib could be effective for patients with KRAS mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically.

• Subject: Animals / Antineoplastic Agents - pharmacology / Cell Line, Tumor / Humans / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Mice / Mutation / Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors / Proto-Oncogene Proteins p21(ras) - genetics / Proto-Oncogene Proteins p21(ras) - metabolism / Xenograft Model Antitumor Assays