Blockade of YAP-TEAD Does Not Overcome Radiation Resistance in Primary Vestibular Schwannoma

Introduction: Vestibular schwannomas (VS) are benign, intracranial tumors arising from Schwann cells of the eighth cranial nerve that may cause hearing loss, dizziness, tinnitus, and/or potentially lethal brainstem compression. An estimated 9-12% of patients receiving radiotherapy for treatment of VS may exhibit radiation resistance, which may be associated with the Hippo/Yes-associated protein (YAP) signaling pathway that has been shown to contribute to radiation resistance in cancer; prior studies have demonstrated that inhibition of YAP-related pathways can sensitize certain tumors to radiotherapy, so we evaluated the efficacy of a YAP inhibitor (YAPi) called YAP-TEAD Inhibitor 1 (Peptide 17) in sensitizing primary VS cells to radiotherapy.

Methods: During 2023, primary VS cells were cultivated from patient-derived VS and cultured on 384-well plates (5000 cells/well; n=6 replicates per treatment condition) and pre-treated with YAP-TEAD inhibitor at 0 and 10 µM concentrations for 24 hours prior to irradiation with 0 or 18 Gy. At 72 hours post-radiation, cell viability was measured. Double stranded DNA breaks were quantified using immunocytochemistry for gamma-H2AX; cell repair was evaluated via measurement of total YAP and phospho-YAP. Primary VS cells were divided into radiation responsive and resistant groups. Data analysis was performed using 95% confidence intervals and two-way analysis of variance.

Results: We identified primary VS cultures that were responsive and resistant to 18 Gy of single fraction radiation using cell-based assays for viability. The addition of YAP-TEAD inhibitor did not significantly enhance radiation-induced DNA damage and cell death in most primary VS cultures. Changes in total YAP and phospho-YAP in each primary VS are obtained and described in the context of cell growth and repair.

Conclusions: YAP-TEAD inhibition did not sensitize primary VS cells to radiation-induced cell death. Further investigations into mechanisms of radiation resistance and other upstream YAP inhibition pathways are needed to assess the potential of YAP blockade as an effective therapy for VS.