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 language | English (US) |
|---|---|
| Pages (from-to) | 2387-2398 |
| Number of pages | 12 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 16 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2017 |
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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 journal › Article
}
TY - JOUR
T1 - Combination therapy with c-Met and Src inhibitors induces caspase-dependent apoptosis of merlin-deficient Schwann cells and suppresses growth of schwannoma cells
AU - Fuse, Marisa A.
AU - Plati, Stephani Klingeman
AU - Burns, Sarah S.
AU - Dinh, Christine T
AU - Bracho, Olena
AU - Yan, Denise
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
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-17-0417
DO - 10.1158/1535-7163.MCT-17-0417
M3 - Article
C2 - 28775147
AN - SCOPUS:85032806857
VL - 16
SP - 2387
EP - 2398
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 11
ER -