Targeting Hippo-MAPK crosstalk in schwannoma: Overcoming resistance with dual inhibition.
- 1Department of Dermatology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
- 2Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
- 3SpringWorks Therapeutics, Stamford, CT 06902, USA.
Abstract
Individuals with NF2-related schwannomatosis develop hallmark tumors called schwannomas that can cause numbness, pain, hearing loss, and balance issues. There are currently no FDA-approved drugs for schwannoma. Radiation and surgical removal, which can cause nerve damage, are the mainstay treatment options. Schwannomas arise from Schwann cells harboring mutations in the gene NF2. Functional loss of NF2 results in dysregulation of a number of signaling pathways known to play a role in schwannomagenesis, including the Hippo and MAPK pathways. We previously reported that Hippo pathway dysregulation in a genetic mouse model causes development of multiple schwannomas that recapitulate the human tumors, and that further activation of RAS/MAPK pathway via Nf1 deletion in these mice increased tumor burden and reduced overall survival. Here, we show that combined inhibition of dysregulated Hippo signaling and MAPK kinase signaling using a pan-TEAD inhibitor and a MEK inhibitor, respectively, is more effective at slowing tumor growth than either inhibitor alone. Our findings provide support for clinical testing of a pan-TEAD inhibitor plus a MEK inhibitor combination treatment for schwannoma.
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BibTeX
@article{chen2026targeting,
title = {{Targeting Hippo-MAPK crosstalk in schwannoma: Overcoming resistance with dual inhibition.}},
author = {Zhiguo Chen and Ling Zhao and Tracey Shipman and Yong Wang and Renée M McKay and Lei Chen and Lu Q Le},
journal = {Molecular therapy. Oncology},
year = {2026},
month = oct,
doi = {10.1016/j.omton.2026.201356},
url = {https://europepmc.org/article/MED/42921245},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Targeting Hippo-MAPK crosstalk in schwannoma: Overcoming resistance with dual inhibition.
AU - Zhiguo Chen
AU - Ling Zhao
AU - Tracey Shipman
AU - Yong Wang
AU - Renée M McKay
AU - Lei Chen
AU - Lu Q Le
PY - 2026
DA - 2026/10/06
JO - Molecular therapy. Oncology
DO - 10.1016/j.omton.2026.201356
UR - https://europepmc.org/article/MED/42921245
AB - Individuals with NF2-related schwannomatosis develop hallmark tumors called schwannomas that can cause numbness, pain, hearing loss, and balance issues. There are currently no FDA-approved drugs for schwannoma. Radiation and surgical removal, which can cause nerve damage, are the mainstay treatment options. Schwannomas arise from Schwann cells harboring mutations in the gene NF2. Functional loss of NF2 results in dysregulation of a number of signaling pathways known to play a role in schwannomagenesis, including the Hippo and MAPK pathways. We previously reported that Hippo pathway dysregulation in a genetic mouse model causes development of multiple schwannomas that recapitulate the human tumors, and that further activation of RAS/MAPK pathway via Nf1 deletion in these mice increased tumor burden and reduced overall survival. Here, we show that combined inhibition of dysregulated Hippo signaling and MAPK kinase signaling using a pan-TEAD inhibitor and a MEK inhibitor, respectively, is more effective at slowing tumor growth than either inhibitor alone. Our findings provide support for clinical testing of a pan-TEAD inhibitor plus a MEK inhibitor combination treatment for schwannoma.
SN - 2950-3299
ER -