Combination Therapy With C-Met And Src Inhibitors Induces Caspase-Dependent Apoptosis Of Merlin-Deficient Schwann Cells And Suppresses Growth Of Schwannoma Cells

Abstract

Neurofibromatosis type 2 (NF2) is a nervous system tumor disorder caused by inactivation of the merlin tumor suppressor encoded by the NF2 gene. Bilateral vestibular schwannomas are a diagnostic hallmark of NF2. Mainstream treatment options for NF2-associated tumors have been limited to surgery and radiotherapy; however, off-label uses of targeted molecular therapies are becoming increasingly common. Here, we investigated drugs targeting two kinases activated in NF2-associated schwannomas, c-Met and Src. We demonstrated that merlin-deficient mouse Schwann cells (MD-MSC) treated with the c-Met inhibitor, cabozantinib, or the Src kinase inhibitors, dasatinib and saracatinib, underwent a G1 cell-cycle arrest. However, when MD-MSCs were treated with a combination of cabozantinib and saracatinib, they exhibited caspase-dependent apoptosis. The combination therapy also significantly reduced growth of MD-MSCs in an orthotopic allograft mouse model by greater than 80% of vehicle. Moreover, human vestibular schwannoma cells with NF2 mutations had a 40% decrease in cell viability when treated with cabozantinib and saracatinib together compared with the vehicle control. This study demonstrates that simultaneous inhibition of c-Met and Src signaling in MD-MSCs triggers apoptosis and reveals vulnerable pathways that could be exploited to develop NF2 therapies.

Publication Date

11-1-2017

Publication Title

Molecular Cancer Therapeutics

Volume

16

Issue

11

Number of Pages

2387-2398

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1158/1535-7163.MCT-17-0417

Socpus ID

85032806857 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85032806857

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