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A subset of flavaglines inhibits KRAS nanoclustering and activation

Hajime Yurugi1, Yinyin Zhuang2, Farid A Siddiqui3

  • 1Cell Biology Unit, University Medical Center Mainz, Johannes Gutenberg University, D 55131 Mainz, Germany.

Journal of Cell Science
|June 6, 2020
PubMed

Insights

Natural anti-cancer drugs called flavaglines inhibit KRAS oncogene activation by disrupting its interaction with prohibitins. This finding offers a promising new strategy for developing targeted KRAS inhibitors for cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • RAS oncogenes, particularly KRAS, are frequently mutated in human cancers.
  • Flavaglines are natural compounds with anti-tumour properties that interact with prohibitins.

Purpose of the Study:

  • To investigate the anti-cancer effects of flavaglines on RAS oncogene activation.
  • To explore the mechanism by which flavaglines inhibit KRAS.

Main Methods:

  • Cell-based assays to measure RAS GTP loading and oncogene activation.
  • Analysis of KRAS nanoclustering at the plasma membrane.
  • Prohibitin interaction studies using biochemical and genetic approaches.
  • In vivo studies using KRAS-driven mouse models of non-small-cell lung carcinoma (NSCLC).

Main Results:

  • Flavaglines, including rocaglamide, inhibit RAS GTP loading and KRAS activation at nanomolar concentrations.
  • Rocaglamide specifically inhibits KRAS nanoclustering at phospholipid-enriched plasma membrane domains.
  • Plasma membrane-associated prohibitins interact with KRAS, and rocaglamide disrupts these interactions.
  • Flavagline treatment inhibits oncogenic KRAS-mutated cell growth and reduces NSCLC tumor nodules in mice without severe side effects.

Conclusions:

  • Flavaglines are potent inhibitors of KRAS activation and oncogenic signaling.
  • Targeting the prohibitin-KRAS interaction with flavaglines represents a promising therapeutic strategy for KRAS-mutated cancers.
  • Flavagline derivatives warrant further development as specific KRAS inhibitors for clinical application.
Keywords:
FlavaglineKRASLipid nanoclusterPhospholipidProhibitinRocaglamide

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