RAS Mutation-Specific Responses to Paralog- and State-Selective RAS Inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• A high therapeutic index is crucial for effective cancer therapies, requiring potent inhibition of oncogenic signaling in tumor cells with minimal impact on normal cells.
• Recent advancements include diverse RAS-targeting inhibitors, such as mutant-specific (KRAS G12C, KRAS G12D) and paralog- or state-selective inhibitors.
• Non-mutant-specific RAS inhibition strategies include targeting guanine nucleotide exchange factors (SHP2, SOS1), KRAS-OFF inhibitors, and active-state RAS(ON) inhibitors.

Purpose of the Study:

• To define the signaling inhibition index (SII) for state- and paralog-selective RAS inhibitors.
• To evaluate the differential suppression of oncogenic signaling between RAS-mutant and normal cells across various models.
• To inform the design and clinical application of RAS-targeted therapies for improved tumor selectivity and outcomes.

Main Methods:

• Evaluation of the signaling inhibition index (SII) for state- and paralog-selective RAS inhibitors.
• Testing across diverse RAS-mutant and RAS-wild-type cellular and xenograft models.
• Comparative analysis of different RAS inhibition strategies: guanine nucleotide exchange-OFF, KRAS-OFF, and active-state RAS(ON) inhibitors.

Main Results:

• Guanine nucleotide exchange-OFF inhibitors showed neutral or negative SII, with reduced MAPK suppression in KRAS G12X cells versus wild-type.
• KRAS G13D models, particularly with NF1 loss, demonstrated low sensitivity; SHP2 plus MEK inhibition yielded low selectivity.
• RAS Q61X models were resistant due to MEK inhibitor-induced NRAS reactivation and altered SHP2 conformations; KRAS-OFF inhibitors showed higher selectivity.
• Active-state RAS(ON) inhibitors exhibited broader activity but narrow selectivity.
• Sensitivity to mutant-specific inhibitors largely overlapped with state-selective agents, indicating poor response to current RAS inhibitors for most RAS-mutant tumors.

Conclusions:

• Current state- and paralog-selective RAS inhibitors often lack sufficient tumor selectivity, as indicated by their signaling inhibition index (SII).
• Guanine nucleotide exchange-OFF and active-state RAS(ON) inhibitors demonstrate limitations in efficacy and selectivity across different RAS mutations and contexts.
• Most RAS-mutant tumors are predicted to have a poor response to currently available RAS inhibitors, necessitating further development of more selective therapeutic strategies.