Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis

被引:36
作者
Cooper, Jonathan [1 ,2 ,3 ]
Xu, Qingwen [4 ,5 ]
Zhou, Lu [6 ,7 ]
Pavlovic, Milica [1 ,2 ,4 ,5 ]
Ojeda, Virginia [1 ,2 ]
Moulick, Kamalika [1 ,2 ]
de Stanchina, Elisa [8 ]
Poirier, John T. [9 ,10 ]
Zauderer, Marjorie [9 ,10 ,11 ]
Rudin, Charles M. [9 ,10 ]
Karajannis, Matthias A. [12 ]
Hanemann, C. Oliver [6 ,7 ]
Giancotti, Filippo G. [4 ,5 ]
机构
[1] Mem Sloan Kettering Canc Ctr, Cell Biol Program, 1275 York Ave, New York, NY 10021 USA
[2] Mem Sloan Kettering Canc Ctr, Ctr Metastasis Res, Sloan Kettering Inst Canc Res, 1275 York Ave, New York, NY 10021 USA
[3] Weill Cornell Med Coll, Weill Cornell Grad Sch Med Sci, New York, NY USA
[4] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA
[5] Univ Texas MD Anderson Canc Ctr, David H Koch Ctr Appl Res Genitourinary Canc, Houston, TX 77030 USA
[6] Plymouth Univ, Peninsula Sch Med, Plymouth, Devon, England
[7] Plymouth Univ, Peninsula Sch Dent, Plymouth, Devon, England
[8] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst Canc Res, Antitumor Assessment Core Facil, 1275 York Ave, New York, NY 10021 USA
[9] Mem Hosp, Mem Sloan Kettering Canc Ctr, Thorac Oncol Serv, New York, NY USA
[10] Mem Hosp, Mem Sloan Kettering Canc Ctr, Druckenmiller Ctr Lung Canc Res, New York, NY USA
[11] Weill Cornell Med Coll, New York, NY USA
[12] Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave, New York, NY 10021 USA
关键词
MALIGNANT PLEURAL MESOTHELIOMA; HERPES-SIMPLEX-VIRUS; NEUROFIBROMATOSIS TYPE-2; ACTIVATION; GROWTH; CELLS; SCHWANNOMA; PATHWAY; COMPLEX; KINASE;
D O I
10.1158/1535-7163.MCT-16-0821
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 CRL4(DCAF1), thereby inhibiting the Hippo pathway component Lats. Here, we show that MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, suppresses CRL4(DCAF1) 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 CRL4(DCAF1). 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. (C)2017 AACR.
引用
收藏
页码:1693 / 1704
页数:12
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