Abstract

Neurofibromatosis type 2 (NF2) is an inherited disorder characterized by bilateral vestibular schwannomas (VS) that arise from neoplastic Schwann cells (SCs). NF2-associated VSs are often accompanied by meningioma (MN), and the majority of NF2 patients show loss of the NF2 tumor suppressor. mTORC1 and mTORC2-specific serum/glucocorticoid-regulated kinase 1 (SGK1) are constitutively activated in MN with loss of NF2. In a recent high-throughput kinome screen in NF2-null human arachnoidal and meningioma cells, we showed activation of EPH RTKs, c-KIT, and SFK members independent of mTORC1/2 activation. Subsequently, we demonstrated in vitro and in vivo efficacy of combination therapy with the dual mTORC1/2 inhibitor AZD2014 and the multi-kinase inhibitor dasatinib. For these reasons, we investigated activated mTORC1/2 and EPH receptor-mediated signaling in sporadic and NF2-associated VS. Using primary human VS cells and a mouse allograft model of schwannoma, we evaluated the dual mTORC1/2 inhibitor AZD2014 and the tyrosine kinase inhibitor dasatinib as monotherapies and in combination. Escalating dose-response experiments on primary VS cells grown from 15 human tumors show that combination therapy with AZD2014 and dasatinib is more effective at reducing metabolic activity than either drug alone and exhibits a therapeutic effect at a physiologically reasonable concentration (~0.1 µM). In vivo, while AZD2014 and dasatinib each inhibit tumor growth alone, the effect of combination therapy exceeds that of either drug. Co-targeting the mTOR and EPH receptor pathways with these or similar compounds may constitute a novel therapeutic strategy for VS, a condition for which there is no FDA-approved pharmacotherapy.

Details

Title
Combination therapy with mTOR kinase inhibitor and dasatinib as a novel therapeutic strategy for vestibular schwannoma
Author
Sagers, Jessica E 1 ; Beauchamp, Roberta L 2 ; Zhang, Yanling 3 ; Vasilijic Sasa 4 ; Wu Limeng 5 ; DeSouza, Patrick 2 ; Seist, Richard 4 ; Zhou Wenjianlong 6 ; Xu, Lei 6   VIAFID ORCID Logo  ; Ramesh Vijaya 7 ; Stankovic, Konstantina M 1 

 Massachusetts Eye and Ear and Harvard Medical School, Eaton-Peabody Laboratories and Department of Otolaryngology – Head and Neck Surgery, Boston, USA (GRID:grid.39479.30) (ISNI:0000 0000 8800 3003); Harvard Medical School, Program in Speech and Hearing Bioscience and Technology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Harvard Medical School, Harvard Program in Therapeutic Science, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
 Massachusetts General Hospital and Harvard Medical School, Center for Genomic Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
 Massachusetts General Hospital and Harvard Medical School, Edwin L. Steele Laboratories, Department of Radiation Oncology, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Huazhong University of Science and Technology, Cancer Center, Union Hospital, Tongji Medical College, Wuhan, China (GRID:grid.33199.31) (ISNI:0000 0004 0368 7223) 
 Massachusetts Eye and Ear and Harvard Medical School, Eaton-Peabody Laboratories and Department of Otolaryngology – Head and Neck Surgery, Boston, USA (GRID:grid.39479.30) (ISNI:0000 0000 8800 3003) 
 Massachusetts General Hospital and Harvard Medical School, Edwin L. Steele Laboratories, Department of Radiation Oncology, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Central South University, Department of Oral and Maxillofacial Surgery, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164) 
 Massachusetts General Hospital and Harvard Medical School, Edwin L. Steele Laboratories, Department of Radiation Oncology, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
 Massachusetts General Hospital and Harvard Medical School, Center for Genomic Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Massachusetts General Hospital and Harvard Medical School, Department of Neurology, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2372862356
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.