A novel protein RASON encoded by a lncRNA controls oncogenic RAS signaling in KRAS mutant cancers

Mutations of the RASoncogene are found in around 30% of all human cancers yet direct targeting of RAS is still considered clinically impractical except for the KRASG12Cmutant. Here we report that RAS-ON(RASON), a novel protein encoded by the long intergenic non-protein coding RNA 00673 (LINC00673), is a positive regulator of oncogenic RAS signaling. RASON is aberrantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) patients, and it promotes proliferation of human PDAC cell lines in vitro and tumor growth in vivo. CRISPR/Cas9-mediated knockout of Rasonin mouse embryonic fibroblasts inhibits KRAS-mediated tumor transformation. Genetic deletion of Rasonabolishes oncogenic KRAS-driven pancreatic and lung cancer tumorigenesis in LSL-KrasG12D; Trp53R172H/+mice. Mechanistically, RASON directly binds to KRASG12D/Vand inhibits both intrinsic and GTPase activating protein (GAP)-mediated GTP hydrolysis, thus sustaining KRASG12D/Vin the GTP-bound hyperactive state. Therapeutically, deprivation of RASON sensitizes KRAS mutant pancreatic cancer cells and patient-derived organoids to EGFR inhibitors. Our findings identify RASON as a critical regulator of oncogenic KRAS signaling and a promising therapeutic target for KRAS mutant cancers.