Priority Research Papers:
Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors
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Lynsey Vaughan1,9, Paul A. Clarke2, Karen Barker1, Yvan Chanthery3, Clay W. Gustafson3, Elizabeth Tucker1, Jane Renshaw1, Florence Raynaud4, Xiaodun Li1,11, Rosemary Burke5, Yann Jamin6, Simon P. Robinson6, Andrew Pearson1, Michel Maira7,10, William A. Weiss3, Paul Workman2 and Louis Chesler1,2,8
1 Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey, UK
2 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
3 Department of Neurology, Pediatrics, Neurosurgery, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
4 Cancer Research UK Cancer Therapeutics Unit, Clinical Pharmacology and Trials Team, Sutton, Surrey, UK
5 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
6 Cancer Research UK & Engineering and Physical Sciences Research Council Cancer Imaging Centre, The Institute of Cancer Research, Sutton, Surrey, UK
7 Novartis Pharma AG, Basel, Switzerland
8 The Royal Marsden NHS Trust, Children and Young People’s Unit, Sutton, Surrey, UK
9 Present address: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
10 Present address: Basilea Pharmaceutica International AG, Basel, Switzerland
11 Present address: MRC Cancer Unit, University of Cambridge, Cambridge, UK
Louis Chesler, email:
Keywords: neuroblastoma, mTOR, MYC, MYCN, PI3-kinase
Received: April 29, 2016 Accepted: June 01, 2016 Published: July 12, 2016
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.
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