Abstract 380P
Background
RRAS and RRAS2 belong to the RAS-family GTPases and share sequence homology with KRAS, NRAS, and HRAS. Whereas mutations in KRAS, HRAS and NRAS arewell-known oncogenic drivers in lung adenocarcinoma (LUAD), similar mutations in RRAS and RRAS2 have not been previously well characterized in LUAD.
Methods
We analyzed data on 8,488 patients with LUAD profiled by MSK-IMPACT targeted DNA sequencing and performed functional studies for oncogenicity.
Results
RRASQ87L and RRAS2Q72L mutations were identified in ∼0.45% of LUAD and were mutually exclusive with other receptor tyrosine kinase and MAPK drivers. RRASQ87L and RRAS2Q72L promoted IL3-independent growth in vitro in murine IL3-dependent human bronchial epithelial cells (HBEC) and xenograft tumor growth in NOD SCID gamma (NSG) immunocompromised mice. Further supporting the oncogenic capacity of RRAS/RRAS2 mutations, HBEC expressing these mutations formed tumors in NSG mice. Murine Ba/F3 and HBEC cells expressing these mutations exhibited enhanced activation of the RAS-MAPK and PI3K-AKT pathways. Growth of HBEC and Ba/F3 cells expressing RRAS or RRAS2 mutations was sensitive to inhibitors of ERK1/2 (ulixertinib, SCH772984), MEK1/2 (binimetinib), and RAS (RMC-6236). Treatment of HBEC cells expressing RRAS or RRAS2 mutations with RMC-6236 attenuated ERK1/2, p90 RSK and p70 S6K phosphorylation and inhibited cell growth. RMC-6236 inhibited the growth of HBEC-RRAS2Q72L xenograft tumors in a dose-dependent manner. RRASQ87L and RRAS2Q72L are oncogenic in LUAD and are mutually exclusive with other known lung cancer drivers. Notably, the novel pan-RAS inhibitor RMC-6236 reduced RRAS and RRAS2-driven tumor growth in vivo.
Conclusions
Our findings suggest that patients with RRAS/RRAS2-mutant tumors are likely to derive benefit from RMC-6236 (NCT05379985). Finally, the results are relevant beyond LUAD, as RRAS2 Q72L mutations are also seen in endometrial and ovarian cancers, as well as germ cell tumors.
Funding
Has not received any funding
Disclosure
All authors have declared no conflicts of interest.