Targeting Hippo-MAPK crosstalk in schwannoma: Overcoming resistance with dual inhibition

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.