TY - JOUR
T1 - Combined inhibition of NEDD8-activating enzyme and mTOR suppresses NF2 loss–driven tumorigenesis
AU - Cooper, Jonathan
AU - Xu, Qingwen
AU - Zhou, Lu
AU - Pavlovic, Milica
AU - Ojeda, Virginia
AU - Moulick, Kamalika
AU - De Stanchina, Elisa
AU - Poirier, John T.
AU - Zauderer, Marjorie
AU - Rudin, Charles M.
AU - Karajannis, Matthias A.
AU - Hanemann, C. Oliver
AU - Giancotti, Filippo G.
N1 - Publisher Copyright:
©2017 AACR.
PY - 2017/8
Y1 - 2017/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85027139036&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85027139036&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-16-0821
DO - 10.1158/1535-7163.MCT-16-0821
M3 - Article
C2 - 28468780
AN - SCOPUS:85027139036
SN - 1535-7163
VL - 16
SP - 1693
EP - 1704
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 8
ER -