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

Ajinkya Revandkar, Maria Luna Perciato, Alberto Toso, Abdullah Alajati, Jingjing Chen, Hermeto Gerber, Mitko Dimitrov, Andrea Rinaldi, Nicolas Delaleu, Emiliano Pasquini, Rocco D’Antuono, Sandra Pinton, Marco Losa, Letizia Gnetti, Alberto Arribas, Patrick Fraering, Francesco Bertoni, Alain Nepveu and Andrea Alimonti ()
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Ajinkya Revandkar: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Maria Luna Perciato: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Alberto Toso: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Abdullah Alajati: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Jingjing Chen: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Hermeto Gerber: Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Mitko Dimitrov: Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Andrea Rinaldi: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Nicolas Delaleu: Broegelmann Research Laboratory, University of Bergen
Emiliano Pasquini: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Rocco D’Antuono: Institute for Research in Biomedicine, University of Italian Switzerland, Via Vincenzo Vela 6, Bellinzona 6500, Switzerland
Sandra Pinton: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Marco Losa: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Letizia Gnetti: Pathology Unit, University Hospital of Parma
Alberto Arribas: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Patrick Fraering: Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Francesco Bertoni: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
Alain Nepveu: Rosalind and Morris Goodman Cancer Research Center, Biochemistry and Medicine, McGill University
Andrea Alimonti: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms13719

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