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 Citations (Scopus)

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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Neurofibromin 2
Neurofibromatosis 2
Caspase Inhibitors
Schwann Cells
Neurilemmoma
Apoptosis
Growth
Acoustic Neuroma
Therapeutics
Neurofibromatosis 2 Genes
Molecular Targeted Therapy
Nervous System Neoplasms
Off-Label Use
G1 Phase Cell Cycle Checkpoints
src-Family Kinases
Drug Delivery Systems
Caspases
Nervous System Diseases
Allografts
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Combination therapy with c-Met and Src inhibitors induces caspase-dependent apoptosis of merlin-deficient Schwann cells and suppresses growth of schwannoma cells. / Fuse, Marisa A.; Plati, Stephani Klingeman; Burns, Sarah S.; Dinh, Christine T; Bracho, Olena; Yan, Denise; Mittal, Rahul; Shen, Rulong; Soulakova, Julia N.; Copik, Alicja J.; Liu, Xue Z; Telischi, Fred F; Chang, Long Sheng; Franco, Maria Clara; Fernandez-Valle, Cristina.

In: Molecular Cancer Therapeutics, Vol. 16, No. 11, 01.11.2017, p. 2387-2398.

Research output: Contribution to journalArticle

Fuse, Marisa A. ; Plati, Stephani Klingeman ; Burns, Sarah S. ; Dinh, Christine T ; Bracho, Olena ; Yan, Denise ; Mittal, Rahul ; Shen, Rulong ; Soulakova, Julia N. ; Copik, Alicja J. ; Liu, Xue Z ; Telischi, Fred F ; Chang, Long Sheng ; Franco, Maria Clara ; Fernandez-Valle, Cristina. / Combination therapy with c-Met and Src inhibitors induces caspase-dependent apoptosis of merlin-deficient Schwann cells and suppresses growth of schwannoma cells. In: Molecular Cancer Therapeutics. 2017 ; Vol. 16, No. 11. pp. 2387-2398.
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AU - Burns, Sarah S.

AU - Dinh, Christine T

AU - Bracho, Olena

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AU - Mittal, Rahul

AU - Shen, Rulong

AU - Soulakova, Julia N.

AU - Copik, Alicja J.

AU - Liu, Xue Z

AU - Telischi, Fred F

AU - Chang, Long Sheng

AU - Franco, Maria Clara

AU - Fernandez-Valle, Cristina

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