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Updated: Apr 4, 2026

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans
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Published on: October 5, 2020

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Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR

Linara Gabitova1, Diana Restifo2, Andrey Gorin1

  • 1Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Tatarstan 420000, Russia.

Cell Reports
|September 8, 2015
PubMed

Insights

Inhibiting cholesterol synthesis enzymes (NSDHL) in KRAS-driven skin tumors reduced cancer growth. This metabolic interference strategy also involved liver X receptor (LXR) activation and epidermal growth factor receptor (EGFR) signaling.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Meiosis-activating sterols (MAS) are crucial for development and are synthesized via SC4MOL and NSDHL.
  • Oncogenic signaling pathways like EGFR and RAS elevate cellular cholesterol demands, presenting a metabolic vulnerability.

Purpose of the Study:

  • To investigate the therapeutic potential of interfering with cholesterol metabolism in KRAS-driven skin cancer.
  • To explore the interplay between cholesterol homeostasis, LXRα, and EGFR signaling in oncogenesis.

Main Methods:

  • In vivo ablation of Nsdhl in adult keratinocytes expressing KRAS(G12D).
  • Analysis of gene expression (ABC transporters, LDLR) and intracellular cholesterol levels.
  • Assessment of liver X receptor (LXR) α dependency and EGFR signaling interactions.

Main Results:

  • Nsdhl inactivation significantly antagonized skin tumor growth without affecting normal skin.
  • Loss of Nsdhl upregulated ABCA1 and ABCG1, downregulated LDLR, and reduced cholesterol, mediated by LXRα.
  • EGFR signaling counteracted LXRα's effects, while EGFR inhibition synergized with LXRα agonists against cancer cells.

Conclusions:

  • Targeting cholesterol synthesis enzymes (SC4MOL, NSDHL) or activating LXRα represents a viable therapeutic strategy for EGFR-KRAS-driven carcinomas.
  • Metabolic interference with cholesterol homeostasis offers a promising avenue for cancer treatment.

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