Saturation mutagenesis library screening identifies on-target secondary resistance mutations in KRAS^G12D-selective inhibitors.

Authors

Hannan Xie, Gaoming Wang, Zhiqing Yuan, Yanjing Li, Yingbin Liu

Published in

Cancer letters. Pages 218931. Nov 02, 2026. Epub Nov 02, 2026.

Abstract

KRAS is the most frequently mutated oncogene in pancreatic cancer, with over 90% of patients harboring KRAS mutations, approximately 45% of which are G12D substitutions. The development of KRAS^G12D selective inhibitors, such as HRS-4642, MRTX1133 and RMC-9805, has brought new hope for treating this patient population. However, the clinical efficacy of these inhibitors is limited by the emergence of acquired resistance, the mechanisms of which remain incompletely understood. Our study employed a KRAS saturation mutagenesis library to systematically map the landscape of KRAS mutations conferring resistance to HRS-4642 and MRTX1133. We identified several secondary mutations-including R73P, E63P, D69W, and M72K-that confer resistance to both inhibitors, while M72H was found specifically resistant to HRS-4642. We further characterized the impact of these mutations on KRAS downstream signaling and performed structural modeling of the mutant proteins. Through molecular dynamics simulations, we suggested that the R73P mutation, although distant from the binding pocket, is predicted to exert a global dynamic effect on the allosteric site, thereby disrupting inhibitor-protein interactions. This suggests the existence of a novel class of KRAS resistance mutations and a previously unrecognized mechanism of acquired resistance to KRAS-targeted therapies. Furthermore, we identified Y64W, A59G, and R73P as mutations that concurrently confer resistance to the tri-complex inhibitor RMC-9805, as well as to the allosteric inhibitors MRTX1133 and HRS-4642. This comprehensive analysis delineates the global landscape of secondary resistance mutations to KRAS^G12D-selective inhibitors.

PMID:
42971499
Bibliographic data and abstract were imported from PubMed on 03 Nov 2026.

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