Chaperone directed heterobifunctional molecules circumvent KRASG12C inhibitor resistance
While KRAS<sup>G12C</sup> inhibitors have shown promising results in clinical activity, acquired resistance remains a significant barrier to durable responses. Combination therapies have been explored to improve the efficacy of KRAS<sup>G12C</sup> inhibitors; however, their use is often restricted due to toxicity and limitations in clinically amenable dosing schedules. Transcriptomic profiling and functional assays on acquired resistant models to adagrasib identified an enrichment of HSP90 client proteins in resistant phenotypes, suggesting a therapeutic vulnerability. To address the finding, RNK07421, a novel heterobifunctional molecule, was developed to simultaneously target KRAS<sup>G12C</sup> and HSP90-client oncoproteins. Structural and biochemical analyses demonstrated that RNK07421 disrupts KRAS<sup>G12C</sup> interactions by inducing a non-natural interface with HSP90, thereby impairing oncogenic signaling. In vitro, RNK07421 effectively suppressed ERK reactivation and reduced viability in KRAS<sup>G12C</sup>-mutant cell lines exhibiting either intrinsic or acquired resistance. In vivo, RNK07421 significantly reduced tumor burden in xenograft models, outperforming both monotherapies and combination therapies. These findings highlight dual KRAS<sup>G12C</sup> and HSP90 inhibition as a promising strategy to overcome resistance in KRAS<sup>G12C</sup>-driven cancers.
Authors
- Qiyue Luan (ORCID: https://orcid.org/0000-0003-4047-9856)
- Takeshi Shimamura (ORCID: https://orcid.org/0000-0002-5402-7204)
- Khaled Abdelhady (ORCID: https://orcid.org/0000-0002-5938-6986)
- Guoqiang Wang (ORCID: https://orcid.org/0000-0001-5732-8144)
- Chenghao Ying
- Christian Ascoli (ORCID: https://orcid.org/0000-0002-7424-2710)
- Ian Papautsky (ORCID: https://orcid.org/0000-0002-1396-9625)
- Kevin P. Foley (ORCID: https://orcid.org/0000-0001-5148-7689)
- Inés Pulido (ORCID: https://orcid.org/0000-0002-1637-6702)
- Laura C. Gunder (ORCID: https://orcid.org/0000-0002-7619-058X)
- Weiwen Ying (ORCID: https://orcid.org/0000-0002-5879-3782)
- Yuetong Sun
- Julián Carretero (ORCID: https://orcid.org/0000-0001-7269-8506)
- Thomas L. Prince (ORCID: https://orcid.org/0000-0003-3333-9599)
- Yan Dai (ORCID: https://orcid.org/0009-0009-4130-9753)
- Sara Pastor-Puente
- Jinhua Li (ORCID: https://orcid.org/0000-0003-1110-7471)
- Yaya Wang (ORCID: https://orcid.org/0000-0001-7947-701X)
- Malek G. Massad
Institutions
- Universitat de València (ES)
- University of Illinois Chicago (US)
- University of Chicago (US)
- RaNA Therapeutics (United States) (US)
- University of Illinois Hospital & Health Sciences System (US)
- NKT Therapeutics (United States) (US)
Publication Details
- Journal
- Cancer Letters
- Published
- 2025-04-08
- DOI
- https://doi.org/10.1016/j.canlet.2025.217691
- Citations
- 1
- Primary Topic
- Heat shock proteins research
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- U.S. Department of Defense
- Ministerio de Ciencia, Innovación y Universidades
- Fundación Domingo Martínez
- National Institutes of Health
- Cancer Center, University of Illinois at Chicago