and mutations are recurrent oncogenic drivers in lung cancer and are sensitive to the pan-RAS inhibitor RMC-6236.

[INTRODUCTION] and encode a subfamily of RAS-like small GTPases that share considerable structural and functional similarities with , , and Whether homologous / mutations are oncogenic and actionable drivers in lung cancer remains underexplored.

[METHODS] An institutional cohort of 8,488 non-small cell lung carcinomas (NSCLC) sequenced by comprehensive targeted DNA sequencing (MSK-IMPACT) between 2016-2024 was evaluated for / mutations. or were modeled in murine IL3-dependent Ba/F3 cells and immortalized human bronchiolar epithelial cells (HBECs). The oncogenic potential, signaling characteristics, and sensitivity to PI3K and MAPK pathway inhibitors, including the novel pan-RAS inhibitor RMC-6236, were evaluated and .

[RESULTS] or , homologous to KRAS-codon Q61 substitutions, were found in ∼0.45% of NSCLCs (38/8,488), with all but two lacking other MAPK pathway oncogenic drivers. RRAS and RRAS2 mutations transformed Ba/F3 and HBEC cells and robustly activated MAPK and PI3K-mTOR pathway signaling. RMC-6236 suppressed proliferation of RRAS and RRAS2 mutant cell lines, reduced ERK phosphorylation, induced apoptosis, and impeded cell-cycle progression. , RMC-6236 significantly inhibited growth of / -mutant HBEC-derived xenografts.

[CONCLUSIONS] RRAS and RRAS2 are recurrent, oncogenic, and potentially actionable drivers in NSCLC. Our study supports the inclusion of into routine molecular diagnostic panels for precision oncology and provides preclinical rationale for investigating the potential therapeutic utility of pan-RAS inhibitors for patients with RRAS /RRAS2 -mutant lung cancers.

[STATEMENT OF TRANSLATIONAL RELEVANCE] Targeted therapies have transformed standard of care for oncogene-driven non-small cell lung carcinomas (NSCLC), yet a significant subset lacks actionable drivers. We identified recurrent and mutations which are mutually exclusive with other MAPK pathway drivers and found in ∼0.45% of NSCLC, comparable in prevalence to and fusions. In preclinical models, these mutations activate canonical growth signaling, drive tumorigenic phenotypes, and confer sensitivity to RAS/MAPK-directed agents, including the novel pan-RAS inhibitor RMC-6236, currently in trials for patients with solid tumors harboring mutations. These data support and as lung cancer drivers and nominate RRAS/RRAS2-mutant tumors as candidates for pan-RAS-targeted therapeutics. Our findings provide a biologic rationale and preclinical evidence to inform molecular testing paradigms and to prioritize enrollment of patients with RRAS/RRAS2-mutant NSCLC into future clinical trials of pan-RAS inhibitors.