Combination therapy with mTOR kinase inhibitor and dasatinib as a novel therapeutic strategy for vestibular schwannoma.

Scientific Reports
Jessica E SagersKonstantina M Stankovic

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...Continue Reading

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Citations

Apr 5, 2020·Cancers·Longping YaoKoos Hovinga
Nov 21, 2020·International Journal of Clinical Oncology·Zi-Ye GaoSheng-Bao Li
Feb 20, 2021·Neuro-oncology Advances·Yin RenKonstantina M Stankovic
Jun 13, 2021·Otolaryngologic Clinics of North America·Nicole C SchmittSarah K Wise
Jun 15, 2021·Otolaryngologic Clinics of North America·Scott Raskin, Miriam Bornhorst

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Methods Mentioned

BETA
xenograft

Clinical Trials Mentioned

NCT02831257
NCT03071874

Software Mentioned

CompuSyn
Fiji
ImageJ
IncuCyte
SynergyFinder

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