Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis.
Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis.
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DOI：
10.1158/1535-7163.mct-16-0821
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发表时间：
2017-08
影响因子：
5.7
通讯作者：
Giancotti FG
中科院分区：
文献类型：
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作者：
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 FG
NF 2/Merlin的失活导致常染色体显性遗传癌症易感综合征家族性神经纤维瘤病2型（NF 2），并有助于恶性胸膜间皮瘤（MPM）的发展。为了开发针对NF 2突变型肿瘤的靶向治疗，我们利用了最近的认识，即Merlin丢失通过激活E3泛素连接酶CRL 4DCAF 1-从而抑制Hippo通路组分Lats来驱动肿瘤发生。在本研究中，我们发现MLN 4924（一种NEDD 8活化酶（NAE）抑制剂）可抑制NF 2突变肿瘤细胞中的CRL 4 DCAF 1并减弱雅普的活化。此外，MLN 4924使MPM对传统化疗敏感，推测是由于参与DNA修复的cullin-RING泛素连接酶（CRL）的附带抑制。然而，即使与化疗联合，MLN 4924也未表现出显著的临床前活性。进一步分析显示，DCAF 1耗竭或MLN 4924处理不会影响NF 2突变肿瘤细胞中的mTOR超活化，表明Merlin缺失可独立于CRL 4 DCAF 1激活mTOR。有趣的是，MLN 4924与mTOR/PI 3 K抑制剂GDC-0980联合使用可抑制体外以及小鼠和患者来源的异种移植物中NF 2突变肿瘤细胞的生长。这些结果为NAE抑制剂联合mTOR/PI 3 K抑制剂治疗NF 2突变型肿瘤提供了临床前依据。
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). In order 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. Additionally, MLN4924 sensitizes MPM to traditional chemotherapy, presumably as a result of collateral inhibition of cullin-RING ubiquitin ligases (CRLs) 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.