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Peer-reviewedCC BYNature communications

Structural mechanisms underlying resistance to Switch-II pocket inhibitors in KRAS.

  • Matthew J Whitley1
  • Marcin Dyba1
  • Mayukh Chakrabarti1
  • Brian P Smith1
  • Albert H Chan1
  • John-Paul Denson1
  • Simon A Messing1
  • Ken Lin2
  • Gabriel Cornilescu1
  • Trent E Balius1
  • Dwight V Nissley1
  • Frank McCormick1,3
2 more authors
  • Anna E Maciag1
  • Dhirendra K Simanshu4
4 affiliations
  1. 1NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  2. 2BridgeBio Oncology Therapeutics, South San Francisco, CA, USA.
  3. 3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
  4. 4NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. [email protected].
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Abstract

Direct targeting of KRAS through the Switch-II pocket is an effective therapeutic strategy, but acquired resistance limits clinical benefit. We examine clinically observed resistance mutations (R68S, H95Q, Y96C, Y96D and Q99L) arising during KRAS G12C inhibitor therapy using biochemical, structural, computational and cellular approaches. Covalent and noncovalent binding measurements reveal mutation- and inhibitor-specific reductions in drug engagement across inhibitor classes. Structural analyses identify two principal resistance mechanisms: Type I, involving loss of key inhibitor contacts, and Type II, involving stabilization of pocket-occluding Switch-II conformations. Y96D exhibits both mechanisms through nucleotide-dependent non-native intramolecular interactions, whereas R68S primarily exhibits Type I resistance with modest Type II effects on pocket architecture and Switch-region dynamics. Y96C, H95Q and Q99L predominantly exhibit Type I resistance. All mutants retain RAF1 binding, whereas PI3Kα binding is selectively reduced by R68S and Q99L. Together, these findings provide structural insights for understanding on-target resistance to Switch-II pocket inhibitors.

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Cite

BibTeXRIS
BibTeX
@article{whitley2026structural,
  title = {{Structural mechanisms underlying resistance to Switch-II pocket inhibitors in KRAS.}},
  author = {Matthew J Whitley and Marcin Dyba and Mayukh Chakrabarti and Brian P Smith and Albert H Chan and John-Paul Denson and Simon A Messing and Ken Lin and Gabriel Cornilescu and Trent E Balius and Dwight V Nissley and Frank McCormick and Anna E Maciag and Dhirendra K Simanshu},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-78133-4},
  url = {https://europepmc.org/article/MED/42957732},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Structural mechanisms underlying resistance to Switch-II pocket inhibitors in KRAS.
AU  - Matthew J Whitley
AU  - Marcin Dyba
AU  - Mayukh Chakrabarti
AU  - Brian P Smith
AU  - Albert H Chan
AU  - John-Paul Denson
AU  - Simon A Messing
AU  - Ken Lin
AU  - Gabriel Cornilescu
AU  - Trent E Balius
AU  - Dwight V Nissley
AU  - Frank McCormick
AU  - Anna E Maciag
AU  - Dhirendra K Simanshu
PY  - 2026
DA  - 2026/09/29
JO  - Nature communications
DO  - 10.1038/s41467-026-78133-4
UR  - https://europepmc.org/article/MED/42957732
AB  - Direct targeting of KRAS through the Switch-II pocket is an effective therapeutic strategy, but acquired resistance limits clinical benefit. We examine clinically observed resistance mutations (R68S, H95Q, Y96C, Y96D and Q99L) arising during KRAS G12C inhibitor therapy using biochemical, structural, computational and cellular approaches. Covalent and noncovalent binding measurements reveal mutation- and inhibitor-specific reductions in drug engagement across inhibitor classes. Structural analyses identify two principal resistance mechanisms: Type I, involving loss of key inhibitor contacts, and Type II, involving stabilization of pocket-occluding Switch-II conformations. Y96D exhibits both mechanisms through nucleotide-dependent non-native intramolecular interactions, whereas R68S primarily exhibits Type I resistance with modest Type II effects on pocket architecture and Switch-region dynamics. Y96C, H95Q and Q99L predominantly exhibit Type I resistance. All mutants retain RAF1 binding, whereas PI3Kα binding is selectively reduced by R68S and Q99L. Together, these findings provide structural insights for understanding on-target resistance to Switch-II pocket inhibitors.
SN  - 2041-1723
ER  -