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

Cell Res. 2023 Jan;33(1):30-45. doi: 10.1038/s41422-022-00726-7. Epub 2022 Oct 14.


Mutations of the RAS oncogene are found in around 30% of all human cancers yet direct targeting of RAS is still considered clinically impractical except for the KRASG12C mutant. 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 Rason in mouse embryonic fibroblasts inhibits KRAS-mediated tumor transformation. Genetic deletion of Rason abolishes oncogenic KRAS-driven pancreatic and lung cancer tumorigenesis in LSL-KrasG12D; Trp53R172H/+ mice. Mechanistically, RASON directly binds to KRASG12D/V and inhibits both intrinsic and GTPase activating protein (GAP)-mediated GTP hydrolysis, thus sustaining KRASG12D/V in 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal* / metabolism
  • Fibroblasts / metabolism
  • Genes, ras
  • Guanosine Triphosphate
  • Humans
  • Mice
  • Mutation / genetics
  • Pancreatic Neoplasms* / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • RNA, Long Noncoding* / genetics


  • RNA, Long Noncoding
  • Proto-Oncogene Proteins p21(ras)
  • Guanosine Triphosphate
  • KRAS protein, human