Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss–Driven Tumorigenesis
Authors: C Oliver Hanemann
Matthias A Karajannis
John T Poirier
Virginia Ojeda
Kamalika Moulick
Lu Zhou
Marjorie Zauderer
Elisa de Stanchina
Milica Pavlovic
Jonathan Cooper
Qingwen Xu
Charles M Rudin
Filippo G Giancotti
Journal: Molecular cancer therapeutics (2017)
Discipline: CLINICAL MEDICINE
Keywords: NF2; Merlin; cancer; familial neurofibromatosis type 2; malignant pleural mesothelioma
Affiliations: Cell Biology Program and Center for Metastasis Research, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.  ., Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College, New York, New York., Department of Cancer Biology and David H. Koch Center for Applied Research of Genitourinary Cancers, University of Texas MD Anderson Cancer Center, Houston, Texas., Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, United Kingdom., Cell Biology Program and Center for Metastasis Research, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York., Antitumor Assessment Core Facility, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York., Thoracic Oncology Service and Druckenmiller Center for Lung Cancer Research, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, New York., Weill Cornell Medical College, New York, New York., Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York., Department of Cancer Biology and David H. Koch Center for Applied Research of Genitourinary Cancers, University of Texas MD Anderson Cancer Center, Houston, Texas.  .

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. Mol Cancer Ther; 16(8); 1693-704. ©2017 AACR. 

Retracted: No

PubPeer comments:
 Figure 2C. Much more similar than you would expect. https: imgur.com Kqsw4vN , 
 Thank you for pointing out this discrepancy. The CYR61 blot was accidentally duplicated (from left panel) to the right-hand panel in Figure 2C. We have determined that this occurred during final figure production, and the figure with the correct panel is shown here. We are contacting the journal to submit a correction. Jonathan Cooper (on behalf of Filippo Giancotti) ![file] , 
 #2 Any update on this? , 
 #3 We just received notice that the correction is moving forward by the publisher. , 
 #3 The article was corrected online January 7, 2021. The article with corrected Figure 2C can be viewed here: https: mct.aacrjournals.org content 16 8 1693.long ,