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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• RRAS and RRAS2 are RAS-like GTPases similar to KRAS, HRAS, and NRAS.
• Their role as oncogenic drivers in lung cancer is not well understood.

Purpose of the Study:

• To investigate the prevalence and oncogenic potential of RRAS/RRAS2 mutations in non-small cell lung cancer (NSCLC).
• To evaluate the efficacy of the pan-RAS inhibitor RMC-6236 against RRAS/RRAS2-mutant NSCLC.

Main Methods:

• Comprehensive targeted DNA sequencing of 8,488 NSCLCs.
• In vitro and in vivo modeling of RRASQ87L and RRAS2Q72L mutations in cell lines.
• Assessment of signaling pathways (MAPK, PI3K-mTOR) and drug sensitivity (RMC-6236).

Main Results:

• RRASQ87L/RRAS2Q72L mutations were found in ~0.45% of NSCLCs, often without other MAPK drivers.
• These mutations activated MAPK and PI3K-mTOR signaling and transformed cells.
• RMC-6236 inhibited proliferation, reduced ERK phosphorylation, induced apoptosis, and suppressed tumor growth in vivo.

Conclusions:

• RRASQ87L and RRAS2Q72L mutations are recurrent, oncogenic drivers in NSCLC.
• These findings support including RRAS/RRAS2 in molecular diagnostics for precision oncology.
• Preclinical data support investigating pan-RAS inhibitors for RRAS/RRAS2-mutant lung cancers.