title: Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors.
abstract: MYC oncoproteins deliver a potent oncogenic stimulus in several human cancers, making them major targets for drug development, but efforts to deliver clinically practical therapeutics have not yet been realized. In childhood cancer, aberrant expression of MYC and MYCN genes delineates a group of aggressive tumours responsible for a major proportion of pediatric cancer deaths. We designed a chemical-genetic screen that identifies compounds capable of enhancing proteasomal elimination of MYCN oncoprotein. We isolated several classes of compound that selectively kill MYCN expressing cells and we focus on inhibitors of PI3K/mTOR pathway in this study. We show that PI3K/mTOR inhibitors selectively killed MYCN-expressing neuroblastoma tumor cells, and induced significant apoptosis of transgenic MYCN-driven neuroblastoma tumors concomitant with elimination of MYCN protein in vivo. Mechanistically, the ability of these compounds to degrade MYCN requires complete blockade of mTOR but not PI3 kinase activity and we highlight NVP-BEZ235 as a PI3K/mTOR inhibitor with an ideal activity profile. These data establish that MYCN expression is a marker indicative of likely clinical sensitivity to mTOR inhibition, and provide a rationale for the selection of clinical candidate MYCN-destabilizers likely to be useful for the treatment of MYCN-driven cancers.
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey, UK.|Present address: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK.
authors.forename: Lynsey
authors.initials: L
authors.lastname: Vaughan
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Signal Transduction and Molecular Pharmacology Team, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clarke
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Barker
authors.affiliation: Department of Neurology, Pediatrics, Neurosurgery, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Chanthery
authors.affiliation: Department of Neurology, Pediatrics, Neurosurgery, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: Clay W
authors.initials: CW
authors.lastname: Gustafson
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tucker
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Renshaw
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Clinical Pharmacology and Trials Team, Sutton, Surrey, UK.
authors.forename: Florence
authors.initials: F
authors.lastname: Raynaud
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey, UK.|Present address: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors.forename: Xiaodun
authors.initials: X
authors.lastname: Li
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Target Selection and Hit Discovery Team, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Burke
authors.affiliation: Cancer Research UK & Engineering and Physical Sciences Research Council Cancer Imaging Centre, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Yann
authors.initials: Y
authors.lastname: Jamin
authors.affiliation: Cancer Research UK & Engineering and Physical Sciences Research Council Cancer Imaging Centre, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Pearson
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Maira
authors.affiliation: Department of Neurology, Pediatrics, Neurosurgery, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Signal Transduction and Molecular Pharmacology Team, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey, UK.|Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Signal Transduction and Molecular Pharmacology Team, The Institute of Cancer Research, Sutton, Surrey, UK.|The Royal Marsden NHS Trust, Children and Young People's Unit, Sutton, Surrey, UK.
authors.forename: Louis
authors.initials: L
authors.lastname: Chesler
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics* / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011804:Quinolines / Q000737:chemistry; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D019076:Transgenes
chemical_list: D000071679:Glycogen Synthase Kinase 3 beta; D007093:Imidazoles; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D000071447:N-Myc Proto-Oncogene Protein; D019869:Phosphatidylinositol 3-Kinases; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C459801:MYCN protein, human; C546842:MTOR protein, human; C000605506:GSK3B protein, human; C531198:dactolisib
keywords: MYC; MYCN; PI3-kinase; mTOR; neuroblastoma