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Oncogene. 2017 Aug 17;36(33):4778-4789. doi: 10.1038/onc.2017.93. Epub 2017 Apr 17.

Targeting prohibitins with chemical ligands inhibits KRAS-mediated lung tumours.

Author information

1
Molecular Signaling Unit-FZI, Institute of Immunology, University Medical Center Mainz, Mainz, Germany.
2
Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center Mainz, Mainz, Germany.
3
Indivumed GmbH, Hamburg, Germany.
4
Therapeutic Innovation Laboratory, UMR7200, CNRS/University of Strasbourg, Strasbourg, France.
5
Sino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.
6
UCT, Mainz, German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, DKFZ, Heidelberg, Germany.

Abstract

KRAS is one of the most frequently mutated oncogenes in human non-small cell lung cancers (NSCLCs). RAS proteins trigger multiple effector signalling pathways including the highly conserved RAF-MAPK pathway. CRAF, a direct RAS effector protein, is required for KRAS-mediated tumourigenesis. Thus, the molecular mechanisms driving the activation of CRAF are intensively studied. Prohibitin 1 (PHB1) is an evolutionarily conserved adaptor protein and interaction of CRAF with PHB1 at the plasma membrane is essential for CRAF activation. Here, we demonstrate that PHB1 is highly expressed in NSCLC patients and correlates with poor survival. Targeting of PHB1 with two chemical ligands (rocaglamide and fluorizoline) inhibits epidermal growth factor (EGF)/RAS-induced CRAF activation. Consistently, treatment with rocaglamide inhibited proliferation, migration and anchorage-independent growth of KRAS-mutated lung carcinoma cell lines. Surprisingly, rocaglamide treatment inhibited Ras-GTP loading in KRAS-mutated cells as well as in EGF-stimulated cells. Rocaglamide treatment further prevented the oncogenic growth of KRAS-driven lung cancer allografts and xenografts in mouse models. Our results suggest rocaglamide as a RAS inhibitor and that targeting plasma membrane-associated PHB1 with chemical ligands would be a viable therapeutic strategy to combat KRAS-mediated NSCLCs.

PMID:
28414306
DOI:
10.1038/onc.2017.93
[Indexed for MEDLINE]

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