RRAS and RRAS2 Mutations Are Recurrent Oncogenic Drivers in Lung Cancer and Are Sensitive to the Pan-RAS Inhibitor RMC-6236

PURPOSE: 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. EXPERIMENTAL DESIGN: An institutional cohort of 8,488 non-small cell lung carcinomas (NSCLC) sequenced by comprehensive targeted DNA sequencing (MSK-IMPACT) between 2016 and 2024 was evaluated for RRAS/RRAS2 mutations. RRASQ87L or RRAS2Q72L were modeled in murine IL3-dependent Ba/F3 cells and immortalized human bronchiolar epithelial cells (HBEC). The oncogenic potential, signaling characteristics, and sensitivity to MAPK pathway inhibitors, including the novel pan-RAS inhibitor RMC-6236, were evaluated in vitro and in vivo. RESULTS: RRAS Q87L or RRAS2Q72L, 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. RRASQ87L and RRAS2Q72L mutations transformed Ba/F3 cells and HBECs and robustly activated MAPK and PI3K-mTOR pathway signaling. RMC-6236 suppressed proliferation of RRASQ87L- and RRAS2Q72L-mutant cell lines, reduced ERK phosphorylation, induced apoptosis, and impeded cell-cycle progression. In vivo, RMC-6236 significantly inhibited growth of RRASQ87L/RRAS2Q72L-mutant HBEC-derived xenografts. CONCLUSIONS: RRASQ87L and RRAS2Q72L 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 RRASQ87L/RRAS2Q72L-mutant lung cancers.