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 Zhong Liu, Fred F. Telischi, Long Sheng Chang, Maria Clara Franco, Cristina Fernandez-Valle

Research output: Contribution to journalArticle

8 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 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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