Characterization of KRAS<sup>G12C</sup> inhibitor olomorasib single-agent and combination with activity in KRAS<sup>G12C</sup>-mutant models.
basic_science · Level V
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- Record sourced from PubMed, PMID 42082482.
- Also identified by DOI 10.1038/s41467-026-72650-y.
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Abstract
The impact of first-generation covalent KRAS<sup>G12C</sup> 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<sup>G12C</sup> inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRAS<sup>G12C</sup> -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<sup>G12C</sup> even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRAS<sup>G12C</sup> inhibitors. These findings suggest that olomorasib could be effective for patients with KRAS<sup>G12C</sup> mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically.