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

Hema Adhikari1, Walaa E Kattan2,3, Shivesh Kumar4

  • 1Department of Pharmacology & Cancer Biology, Duke University, Durham, NC, USA.

Nature Communications
|September 10, 2021
PubMed

Insights

Researchers discovered a new signaling pathway involving EFR3A and PI4KA that drives KRAS-mutant cancers. Inhibiting this pathway shows therapeutic potential for treating these aggressive tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • RAS gene mutations (HRAS, NRAS, KRAS) occur in 20% of human cancers.
  • Mutated RAS proteins are constitutively active, promoting tumor growth through effector protein binding.

Purpose of the Study:

  • To identify novel vulnerabilities in RAS oncoprotein signaling pathways.
  • To explore the role of EFR3A and PI4KA in KRAS-driven tumorigenesis.

Main Methods:

  • Mining RAS interactomes to identify binding partners.
  • Investigating the function of EFR3A and PI4KA in regulating plasma membrane composition.
  • Assessing the impact of EFR3A/PI4KA disruption on oncogenic signaling and tumor growth.
  • Evaluating the combination therapy of a PI4KA inhibitor with sotorasib.

Main Results:

  • EFR3A was identified as an adapter protein preferentially binding oncogenic KRAS.
  • Disrupting EFR3A or PI4KA decreased plasma membrane levels of phosphatidylinositol-4-phosphate, phosphatidylserine, and KRAS.
  • Inhibition of EFR3A or PI4KA reduced oncogenic signaling and tumorigenesis.
  • A PI4KA inhibitor enhanced the efficacy of the KRASG12C inhibitor sotorasib.

Conclusions:

  • A novel KRAS signaling axis involving EFR3A and PI4KA has been identified.
  • This pathway represents a potential therapeutic target for KRAS-mutant cancers.
  • Combination therapy with PI4KA inhibitors offers a promising clinical strategy.

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