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Oncotarget. 2016 Sep 6;7(36):57525-57544. doi: 10.18632/oncotarget.10544.

Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors.

Author information

1
Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey, UK.
2
Present address: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK.
3
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.
4
Department of Neurology, Pediatrics, Neurosurgery, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
5
Cancer Research UK Cancer Therapeutics Unit, Clinical Pharmacology and Trials Team, Sutton, Surrey, UK.
6
Present address: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
7
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.
8
Cancer Research UK & Engineering and Physical Sciences Research Council Cancer Imaging Centre, The Institute of Cancer Research, Sutton, Surrey, UK.
9
Novartis Pharma AG, Basel, Switzerland.
10
The Royal Marsden NHS Trust, Children and Young People's Unit, Sutton, Surrey, UK.

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.

KEYWORDS:

MYC; MYCN; PI3-kinase; mTOR; neuroblastoma

PMID:
27438153
PMCID:
PMC5295370
DOI:
10.18632/oncotarget.10544
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Research have a commercial interest in the development of PI3 kinase inhibitors, and operate a rewards-to-inventors scheme. FR, PAC and PW have been involved in a commercial collaboration with Yamanouchi (now Astellas Pharma) and with Piramed Pharma and intellectual property arising from the program has been licensed to Genentech. PW was a founder of, consultant to, and Scientific Advisory Board member of Piramed Pharma (acquired by Roche). MM was an employee of Novartis Pharma AG, which is involved in the development of PI3K/mTOR inhibitors.

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