RRAS and RRAS2 mutations are recurrent oncogenic drivers in lung cancer and are sensitive to the pan-RAS inhibitor RMC-6236.

Introduction: RRAS and RRAS2 encode a subfamily of RAS-like small GTPases that share considerable structural and functional similarities with KRAS , HRAS , and NRAS. Whether homologous RRAS / RRAS2 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 RRAS / RRAS2 mutations. RRAS Q87L or RRAS2 Q72L 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 in vitro and in vivo . Results: RRAS Q87L or RRAS2 Q72L , 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 Q87L and RRAS2 Q72L mutations transformed Ba/F3 and HBEC cells and robustly activated MAPK and PI3K-mTOR pathway signaling. RMC-6236 suppressed proliferation of RRAS Q87L and RRAS2 Q72L mutant cell lines, reduced ERK phosphorylation, induced apoptosis, and impeded cell-cycle progression. In vivo , RMC-6236 significantly inhibited growth of RRAS Q87L / RRAS2 Q72L -mutant HBEC-derived xenografts. Conclusions: RRAS Q87L and RRAS2 Q72L are recurrent, oncogenic, and potentially actionable drivers in NSCLC. Our study supports the inclusion of RRAS/RRAS2 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 Q87L /RRAS2 Q72L -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 RRAS Q87L and RRAS2 Q72L mutations which are mutually exclusive with other MAPK pathway drivers and found in ∼0.45% of NSCLC, comparable in prevalence to NTRK and NRG1 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 KRAS mutations. These data support RRAS Q87L and RRAS2 Q72L as bona fide 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.