Combined inhibition of NEDD8-activating enzyme and mTOR suppresses NF2 loss-driven tumorigenesis Journal Article

   

Authors:	Cooper, J.; Xu, Q.; Zhou, L.; Pavlovic, M.; Ojeda, V.; Moulick, K.; De Stanchina, E.; Poirier, J. T.; Zauderer, M.; Rudin, C. M.; Karajannis, M. A.; Hanemann, C. O.; Giancotti, F. G.
Article Title:	Combined inhibition of NEDD8-activating enzyme and mTOR suppresses NF2 loss-driven tumorigenesis
Abstract:	Inactivation of NF2/Merlin causes the autosomal-dominant cancer predisposition syndrome familial neurofibromatosis type 2 (NF2) and contributes to the development of malignant pleural mesothelioma (MPM). To develop a targeted therapy for NF2-mutant tumors, we have exploited the recent realization that Merlin loss drives tumorigenesis by activating the E3 ubiquitin ligase CRL4DCAF1, thereby inhibiting the Hippo pathway component Lats. Here, we show that MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, suppresses CRL4DCAF1 and attenuates activation of YAP in NF2-mutant tumor cells. In addition, MLN4924 sensitizes MPM to traditional chemotherapy, presumably as a result of collateral inhibition of cullin-RING ubiquitin ligases (CRL) involved in DNA repair. However, even in combination with chemotherapy, MLN4924 does not exhibit significant preclinical activity. Further analysis revealed that depletion of DCAF1 or treatment with MLN4924 does not affect mTOR hyperactivation in NF2-mutant tumor cells, suggesting that loss of Merlin activates mTOR independently of CRL4DCAF1. Intriguingly, combining MLN4924 with the mTOR/PI3K inhibitor GDC-0980 suppresses the growth of NF2-mutant tumor cells in vitro as well as in mouse and patient-derived xenografts. These results provide preclinical rationale for the use of NAE inhibitors in combination with mTOR/PI3K inhibitors in NF2-mutant tumors. ©2017 AACR.
Journal Title:	Molecular Cancer Therapeutics
Volume:	16
Issue:	8
ISSN:	1535-7163
Publisher:	American Association for Cancer Research
Date Published:	2017-08-01
Start Page:	1693
End Page:	1704
Language:	English
DOI:	10.1158/1535-7163.mct-16-0821
PROVIDER:	scopus
PUBMED:	28468780
PMCID:	PMC5929164
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85027139036&doi=10.1158%2f1535-7163.MCT-16-0821&partnerID=40&md5=1d830a2c572130a4e22711560f655870
Notes:	Article -- Export Date: 5 September 2017 -- Source: Scopus

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