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Arbour, K. C.

Publications and source records attributed to Arbour, K. C..

2 recordsLinked to original sources
bioRxiv2025

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

IntroductionRRAS 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. MethodsAn 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. RRASQ87L or RRAS2Q72L 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. ResultsRRASQ87L 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 and HBEC cells 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. ConclusionsRRASQ87L 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. Statement of translational relevanceTargeted 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 RRASQ87L and RRAS2Q72L 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 RRASQ87L and RRAS2Q72L 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.

cancer biology↗
bioRxiv2025

Mechanisms of resistance to active state selective tri-complex RAS inhibitors

Tri-complex inhibitors (TCIs) act as molecular glues to recruit cyclophilin A (CYPA) to the active (GTP-bound or ON) conformation of RAS, which in turn prevents the activation of downstream effector proteins like RAF and PI3K. Emerging data demonstrate clinical activity, including tumor regressions, in patients with RAS driven cancers. Despite being promising therapeutic interventions, the mechanisms of resistance in patients treated with these inhibitors remain unknown. Here we studied matched baseline and post-progression specimens from patients treated with the RAS(ON) multi-selective inhibitor daraxonrasib (RMC-6236). Tissue or cell-free DNA specimens were collected from 40 patients with RAS-mutant non-small cell lung, colorectal, or other cancers. Eighteen patients (45%) were found to have acquired alterations in RAS signaling intermediates, including recurrent alterations in KRAS, BRAF, RAF1, MAP2K1/2 and PIK3CA. Preclinical resistance models mirrored the alterations observed in patients. We found that secondary KRAS Y64X mutations caused resistance by disrupting an important pi-pi interaction between KRAS and the indole ring of daraxonrasib, which lowers the affinity of the daraxonrasib:CYPA binary complex for active KRAS. We also identified kinase-dead and low-activity BRAF mutations in samples with acquired resistance. This is puzzling, because TCIs are expected to prevent the interaction between RAS and BRAF, which is needed for hypoactive mutants to dimerize and signal. We now show that RAF dimers are harder to displace from active RAS, as compared to their monomeric forms. Indeed, enhanced RAF dimerization attenuated the ability of TCIs to recruit CYPA to active RAS, resulting in diminished inhibition of oncogenic signaling and tumor growth. Thus, several clinical resistance alterations converge at attenuating the formation of the RAS:daraxonrasib:CYPA tri-complex, either by preventing daraxonrasib binding or by inducing RAF dimers.

cancer biology↗