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. Mol Cancer Ther; 16(11); 2387–98. ©2017 AACR.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 01, 2017
- Source ID
- 10.1158/1535-7163.mct-17-0417
Entities
People
- Alicja J. Copik
- Christine T. Dinh
- Cristina Fernandez-valle
- Denise Yan
- Fred F. Telischi
- Julia N. Soulakova
- Long-Sheng Chang
- Maria Clara Franco
- Marisa A. Fuse
- Olena Bracho
- Rahul Mittal
- Rulong Shen
- Sarah S. Burns
- Stephani Klingeman Plati
- Xue Zhong Liu
Organizations
- Children's Tumor Foundation
- Ohio State University
- United States Department of Defense
- University of Central Florida
- University of Miami