Chaperone directed heterobifunctional molecules circumvent KRAS^G12C inhibitor resistance

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• KRAS G12C inhibitors show clinical activity but acquired resistance limits durable responses.
• Combination therapies for KRAS G12C inhibitors face toxicity and dosing challenges.
• Acquired resistance to adagrasib involves enrichment of HSP90 client proteins, indicating a vulnerability.

Purpose of the Study:

• To develop a novel therapeutic strategy targeting both KRAS G12C and HSP90 to overcome acquired resistance.
• To evaluate the efficacy of the dual inhibitor RNK07421 in preclinical models of KRAS G12C-driven cancers.

Main Methods:

• Developed RNK07421, a heterobifunctional molecule targeting KRAS G12C and HSP90 client oncoproteins.
• Utilized structural and biochemical analyses to understand RNK07421's mechanism of action.
• Assessed in vitro efficacy in KRAS G12C-mutant cell lines and in vivo efficacy in xenograft models.

Main Results:

• RNK07421 disrupts KRAS G12C interactions by inducing a non-natural interface with HSP90, impairing oncogenic signaling.
• RNK07421 suppressed ERK reactivation and reduced viability in resistant KRAS G12C cell lines.
• RNK07421 significantly reduced tumor burden in vivo, outperforming monotherapies and combination therapies.

Conclusions:

• Dual KRAS G12C and HSP90 inhibition is a promising strategy to overcome resistance in KRAS G12C-driven cancers.
• RNK07421 demonstrates potent anti-tumor activity and overcomes resistance mechanisms.
• This approach offers a potential new avenue for durable responses in patients with KRAS G12C-mutant cancers.