title: Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence.
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.
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland.|Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne CH 1011, Switzerland.
authors.forename: Ajinkya
authors.initials: A
authors.lastname: Revandkar
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland.
authors.forename: Maria Luna
authors.initials: ML
authors.lastname: Perciato
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland.
authors.forename: Alberto
authors.initials: A
authors.lastname: Toso
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alajati
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland.|Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne CH 1011, Switzerland.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Hermeto
authors.initials: H
authors.lastname: Gerber
authors.affiliation: Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH 1015, Switzerland.
authors.forename: Mitko
authors.initials: M
authors.lastname: Dimitrov
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rinaldi
authors.affiliation: Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen 5021, Norway.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Delaleu
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Pasquini
authors.affiliation: Institute for Research in Biomedicine, University of Italian Switzerland, Via Vincenzo Vela 6, Bellinzona 6500, Switzerland.
authors.forename: Rocco
authors.initials: R
authors.lastname: D'Antuono
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinton
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Losa
authors.affiliation: Pathology Unit, University Hospital of Parma, Parma 43126, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Gnetti
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland.
authors.forename: Alberto
authors.initials: A
authors.lastname: Arribas
authors.affiliation: 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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Fraering
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
authors.affiliation: Rosalind and Morris Goodman Cancer Research Center, Department of Oncology, Biochemistry and Medicine, McGill University, Montreal, Quebec, Canada H3A1A3.
authors.forename: Alain
authors.initials: A
authors.lastname: Nepveu
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland.|Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne CH 1011, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Alimonti
mesh_terms: D000072198:ADAM17 Protein / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use; D015854:Up-Regulation; D014633:Valine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D051880:Receptors, Notch; D013764:Tetrahydronaphthalenes; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D053829:Amyloid Precursor Protein Secretases; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; D014633:Valine; C550722:nirogacestat