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Targeting prohibitins with chemical ligands inhibits KRAS-mediated lung tumours

Oncogene volume 36, pages 4778–4789 (2017)Cite this article

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A Corrigendum to this article was published on 28 August 2017

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.

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Acknowledgements

We thank Alexandra Dimitrijevic for the excellent technical assistance, and Dr Melzer for her help and advice with the animal experiments. We thank Professors Tyler Jacks, Susan Horwitz, Scott Randell, Channing Der and Ulf Rapp for contributing several constructs and cell lines that are employed in this study. We thank Professor Hartmut Juhl and Dr Bernd Gromoll (Indivumed GmbH) for assistance with the analyses of the NSCLC tissue microarrays. This work is supported through a BIS–PLUS3 fellowship of the Boehringer Ingelheim Stiftuing to KR. KR is a Heisenberg Professor of the DFG (RA1739/4-1) and a GFK fellow. A generous financial support for this work was provided by the ‘Association pour la Recherche sur le Cancer’ to LD. We are also grateful to AAREC Filia Research and the ‘Association Nationale de la Recherche et de la Technologie’ (ANRT) for fellowships to QZ.

Author contributions

HY conceived, designed and performed most of the experiments, analysed, interpreted the data and wrote the manuscript. FM and HB contributed to bioinformatics analyses. CW contributed to the staining and analyses of NSCLC tissue microarray. KD contributed to the design and analysis. QZ and LD contributed to the synthesis of fluorizoline. KR contributed to the conception, design, analysis, interpretation of the data, and wrote the manuscript with input from all the authors and supervised the project.

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Authors and Affiliations

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

    H Yurugi & K Rajalingam

  2. Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center Mainz, Mainz, Germany

    F Marini & H Binder

  3. Indivumed GmbH, Hamburg, Germany

    C Weber & K David

  4. Therapeutic Innovation Laboratory, UMR7200, CNRS/University of Strasbourg, Strasbourg, France

    Q Zhao & L Désaubry

  5. Sino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China

    L Désaubry

  6. UCT, Mainz, German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, DKFZ, Heidelberg, Germany

    K Rajalingam

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  1. H Yurugi
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Correspondence to K Rajalingam.

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Yurugi, H., Marini, F., Weber, C. et al. Targeting prohibitins with chemical ligands inhibits KRAS-mediated lung tumours. Oncogene 36, 4778–4789 (2017). https://doi.org/10.1038/onc.2017.93

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