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<p>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 <i>KRAS</i><sup><i>G12C</i></sup> even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved <i>KRAS</i><sup><i>G12C</i></sup> inhibitors. These findings suggest that olomorasib could be effective for patients with <i>KRAS</i><sup>G12C</sup> mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically.</p>

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Characterization of KRASG12C inhibitor olomorasib single-agent and combination with activity in KRASG12C-mutant models

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月4日

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  • 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,
  • 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,
  • 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

摘要

The impact of first-generation covalent KRASG12C 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 KRASG12C inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRASG12C -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 KRASG12C even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRASG12C inhibitors. These findings suggest that olomorasib could be effective for patients with KRASG12C mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically.