Abrogation of Oncogenic RAS Signaling by a RAS(ON) Inhibitor Doublet Primes Immune-Refractory KRASG12C-Mutant NSCLC...

Area of Science:

• Oncology
• Molecular Biology
• Immunotherapy

Background:

• RAS pathway hyperactivation and targeted therapy resistance are critical challenges in KRAS G12C-mutant non-small cell lung cancer (NSCLC).
• Inactive state-selective KRAS G12C inhibitors face resistance due to increased RAS pathway oncogenic flux.

Purpose of the Study:

• To evaluate the combination of elironrasib (RAS(ON) G12C-selective covalent inhibitor) and daraxonrasib (RAS(ON) multi-selective inhibitor) for maximizing RAS pathway suppression.
• To assess the potential of this RAS(ON) inhibitor doublet to overcome targeted therapy resistance and forestall pathway reactivation in preclinical NSCLC models.
• To investigate the immunomodulatory effects of the RAS(ON) inhibitor doublet in immune-competent preclinical models.

Main Methods:

• Evaluation of elironrasib and daraxonrasib combination in preclinical models of KRAS G12C-mutant NSCLC.
• Assessment of RAS pathway suppression, tumor regression, and resistance mechanisms.
• Analysis of tumor immune recognition, antigen presentation, and tumor microenvironment modulation in immune-competent models.

Main Results:

• The RAS(ON) inhibitor doublet induced profound and sustained tumor regressions in preclinical models.
• Combination therapy overcame resistance associated with increased RAS pathway oncogenic flux, which limits inactive state-selective KRAS G12C inhibitors.
• In immune-competent models, the doublet enhanced tumor immune recognition, boosted antigen presentation, remodeled the suppressive tumor microenvironment, and promoted immune-dependent regressions.
• The regimen sensitized an immuno-refractory model to checkpoint blockade therapy.

Conclusions:

• The combination of elironrasib and daraxonrasib provides a potent strategy for RAS pathway suppression and overcoming resistance in KRAS G12C-mutant NSCLC.
• The RAS(ON) inhibitor doublet exhibits significant immunomodulatory effects, enhancing anti-tumor immunity.
• These findings establish a preclinical rationale for investigating this targeted RAS(ON) inhibitor doublet in combination with immune checkpoint blockade for NSCLC patients.