Combination therapy with c-Met and Src inhibitors induces caspase-dependent apoptosis of merlin-deficient Schwann cells and suppresses growth of schwannoma cells

Marisa A. Fuse, Stephani Klingeman Plati, Sarah S. Burns, Christine T Dinh, Olena Bracho, Denise Yan, Rahul Mittal, Rulong Shen, Julia N. Soulakova, Alicja J. Copik, Xue Z Liu, Fred F Telischi, Long Sheng Chang, Maria Clara Franco, Cristina Fernandez-Valle

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2387-2398
Number of pages12
JournalMolecular Cancer Therapeutics
Volume16
Issue number11
DOIs
StatePublished - Nov 1 2017

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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