2. Academic Validation
  3. Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity

Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity

  • Nat Commun. 2021 Sep 9;12(1):5248. doi: 10.1038/s41467-021-25523-5.
Hema Adhikari 1,  Walaa E Kattan 2 3,  Shivesh Kumar 4,  Pei Zhou 4,  John F Hancock 5 6,  Christopher M Counter 7
Affiliations

Affiliations

  • 1 Department of Pharmacology & Cancer Biology, Duke University, Durham, NC, USA.
  • 2 Integrative Biology & Pharmacology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.
  • 3 The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
  • 4 Department of Biochemistry, Duke University, Durham, NC, USA.
  • 5 Integrative Biology & Pharmacology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA. john.f.hancock@uth.tmc.edu.
  • 6 The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at Houston, Houston, TX, USA. john.f.hancock@uth.tmc.edu.
  • 7 Department of Pharmacology & Cancer Biology, Duke University, Durham, NC, USA. count004@mc.duke.edu.
PMID: 34504076 DOI: 10.1038/s41467-021-25523-5
Abstract

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 KRASG12C inhibitor sotorasib, suggesting a clinical path to exploit this pathway. In sum, we have discovered a distinct KRAS signaling axis with actionable therapeutic potential for the treatment of KRAS-mutant cancers.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-114277
    99.94%, KRAS G12C Inhibitor
    Ras