Skip to main content

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

Publication ,  Journal Article
Adhikari, H; Kattan, WE; Kumar, S; Zhou, P; Hancock, JF; Counter, CM
Published in: Nat Commun
September 9, 2021

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

September 9, 2021

Volume

12

Issue

1

Start / End Page

5248

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Burden
  • Survival Analysis
  • Pyrimidines
  • Pyridines
  • Proto-Oncogene Proteins p21(ras)
  • Piperazines
  • Phosphotransferases (Alcohol Group Acceptor)
  • Phosphatidylserines
  • Phosphatidylinositol Phosphates
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Adhikari, H., Kattan, W. E., Kumar, S., Zhou, P., Hancock, J. F., & Counter, C. M. (2021). Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity. Nat Commun, 12(1), 5248. https://doi.org/10.1038/s41467-021-25523-5
Adhikari, Hema, Walaa E. Kattan, Shivesh Kumar, Pei Zhou, John F. Hancock, and Christopher M. Counter. “Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity.Nat Commun 12, no. 1 (September 9, 2021): 5248. https://doi.org/10.1038/s41467-021-25523-5.
Adhikari H, Kattan WE, Kumar S, Zhou P, Hancock JF, Counter CM. Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity. Nat Commun. 2021 Sep 9;12(1):5248.
Adhikari, Hema, et al. “Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity.Nat Commun, vol. 12, no. 1, Sept. 2021, p. 5248. Pubmed, doi:10.1038/s41467-021-25523-5.
Adhikari H, Kattan WE, Kumar S, Zhou P, Hancock JF, Counter CM. Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity. Nat Commun. 2021 Sep 9;12(1):5248.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

September 9, 2021

Volume

12

Issue

1

Start / End Page

5248

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Burden
  • Survival Analysis
  • Pyrimidines
  • Pyridines
  • Proto-Oncogene Proteins p21(ras)
  • Piperazines
  • Phosphotransferases (Alcohol Group Acceptor)
  • Phosphatidylserines
  • Phosphatidylinositol Phosphates