Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence

Revandkar, Ajinkya; Perciato, Maria Luna; Toso, Alberto; Alajati, Abdullah; Chen, Jingjing; Gerber, Hermeto; Dimitrov, Mitko; Rinaldi, Andrea; Delaleu, Nicolas; Pasquini, Emiliano; D’Antuono, Rocco; Pinton, Sandra; Losa, Marco; Gnetti, Letizia; Arribas, Alberto; Fraering, Patrick; Bertoni, Francesco; Nepveu, Alain; Andrea Alimonti

doi:10.1038/ncomms13719

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Journal article

Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence

Revandkar, Ajinkya Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne CH 1011, Switzerland
Perciato, Maria Luna Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Toso, Alberto Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Alajati, Abdullah Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Chen, Jingjing Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne CH 1011, Switzerland
Gerber, Hermeto Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH 1015, Switzerland - Foundation Eclosion, Plan-Les-Ouates CH 1228, Switzerland - Campus Biotech Innovation Park, Geneva CH 1202, Switzerland
Dimitrov, Mitko Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH 1015, Switzerland
Rinaldi, Andrea Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Delaleu, Nicolas Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen 5021, Norway
Pasquini, Emiliano Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
D’Antuono, Rocco Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Pinton, Sandra Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Losa, Marco Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Gnetti, Letizia Pathology Unit, University Hospital of Parma, Parma 43126, Italy
Arribas, Alberto Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Fraering, Patrick Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH 1015, Switzerland - Foundation Eclosion, Plan-Les-Ouates CH 1228, Switzerland - Campus Biotech Innovation Park, Geneva CH 1202, Switzerland
Bertoni, Francesco Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Nepveu, Alain Rosalind and Morris Goodman Cancer Research Center, Department of Oncology, Biochemistry and Medicine, McGill University, Montreal, Quebec, Canada H3A1A3
Andrea Alimonti Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne CH 1011, Switzerland

12.12.2016

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Nature communications. - 2016, vol. 7, p. 13719

English Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of γ-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro-tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of γ-secretase inhibitors in advanced prostate cancer patients.

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