Chaperone directed heterobifunctional molecules circumvent KRAS^G12C inhibitor resistance

While KRAS^G12C 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^G12C 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^G12C and HSP90-client oncoproteins. Structural and biochemical analyses demonstrated that RNK07421 disrupts KRAS^G12C 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^G12C-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^G12C and HSP90 inhibition as a promising strategy to overcome resistance in KRAS^G12C-driven cancers.