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Targeting prohibitins with chemical ligands inhibits KRAS-mediated lung tumours

H Yurugi1, F Marini2, C Weber3

  • 1Molecular Signaling Unit-FZI, Institute of Immunology, University Medical Center Mainz, Mainz, Germany.

Oncogene
|April 18, 2017
PubMed

Insights

Targeting Prohibitin 1 (PHB1) with rocaglamide inhibits KRAS-mutated non-small cell lung cancer (NSCLC) by blocking CRAF activation and Ras-GTP loading. This suggests PHB1 as a therapeutic target for NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • KRAS mutations are common in non-small cell lung cancer (NSCLC) and drive tumor growth via effector pathways like RAF-MAPK.
  • CRAF activation, essential for KRAS-mediated tumorigenesis, requires interaction with Prohibitin 1 (PHB1) at the plasma membrane.

Purpose of the Study:

  • To investigate the role of PHB1 in NSCLC and evaluate PHB1-targeting ligands, specifically rocaglamide, as a therapeutic strategy.
  • To determine if targeting PHB1 can inhibit KRAS-driven lung cancer progression.

Main Methods:

  • Assessed PHB1 expression in NSCLC patients and correlated it with survival.
  • Utilized chemical ligands (rocaglamide, fluorizoline) to target PHB1 and inhibit EGF/RAS-induced CRAF activation.
  • Evaluated the effects of rocaglamide on cell proliferation, migration, anchorage-independent growth, Ras-GTP loading, and tumor growth in preclinical models.

Main Results:

  • PHB1 is highly expressed in NSCLC and associated with poor survival.
  • Rocaglamide treatment inhibited proliferation, migration, and anchorage-independent growth in KRAS-mutated lung cancer cells.
  • Rocaglamide effectively reduced Ras-GTP loading and suppressed tumor growth in KRAS-driven lung cancer mouse models.

Conclusions:

  • PHB1 is a viable therapeutic target in KRAS-mediated NSCLC.
  • Rocaglamide demonstrates potential as a RAS inhibitor and warrants further investigation for NSCLC treatment.

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