sotorasib and Carcinogenesis

KRAS is the most frequently mutated oncogene and plays a predominant role in driving initiation and progression of multiple cancers. Attempts to degrade the oncogene KRAS

Topics: Carcinogenesis; Humans; Mutation; Neoplasms; Oligopeptides; Oncogenes; Proto-Oncogene Proteins p21(ras)

The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers. These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. To further elucidate how RAS oncoproteins signal, we mined RAS interactomes for potential vulnerabilities. Here we identify EFR3A, an adapter protein for the phosphatidylinositol kinase PI4KA, to preferentially bind oncogenic KRAS. Disrupting EFR3A or PI4KA reduces phosphatidylinositol-4-phosphate, phosphatidylserine, and KRAS levels at the plasma membrane, as well as oncogenic signaling and tumorigenesis, phenotypes rescued by tethering PI4KA to the plasma membrane. Finally, we show that a selective PI4KA inhibitor augments the antineoplastic activity of the KRAS

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents; Carcinogenesis; Cell Line, Tumor; Cell Membrane; Dogs; Enzyme Inhibitors; Epithelial Cells; Female; HEK293 Cells; Humans; Lung Neoplasms; Madin Darby Canine Kidney Cells; Membrane Proteins; Mice; Mice, SCID; Minor Histocompatibility Antigens; Mutation; Pancreatic Neoplasms; Phosphatidylinositol Phosphates; Phosphatidylserines; Phosphotransferases (Alcohol Group Acceptor); Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; Survival Analysis; Tumor Burden; Xenograft Model Antitumor Assays