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.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Cooper J,Xu Q,Zhou L,Pavlovic M,Ojeda V,Moulick K,de Stanchina E,Poirier JT,Zauderer M,Rudin CM,Karajannis MA,Hanemann CO,Giancotti FGdoi
10.1158/1535-7163.MCT-16-0821subject
Has Abstractpub_date
2017-08-01 00:00:00pages
1693-1704issue
8eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-16-0821journal_volume
16pub_type
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