The rise of YAP: A new hope in glioblastoma treatment

Despite advances in cancer treatment, glioblastoma (GBM) remains the most malignant subtype of adult brain tumours, with an overall prognosis of only approximately 18 months. The first-line treatment and current standard of care for GBM, aside from maximum surgical resection, is temozolomide (TMZ). Yet, despite TMZ's initial promising results in improving survival, drug resistance and tumour relapse remain nearly unavoidable. Yes-associated protein (YAP) is a key downstream effector of the Hippo pathway that can translocate to the nucleus to induce the transcriptional enhanced associated domain (TEAD)-mediated expression of genes related to cell growth and proliferation. This makes the Hippo signalling pathway critical in tumorigenesis. Through both in vitro and in vivo models, we investigated the role of YAP in GBM. We found upregulation of YAP in GBM to be associated with poor clinical outcomes, with TMZ-resistant GBM showing greater YAP upregulation compared to chemotherapy-sensitive strains, suggesting its role in driving chemoresistance. When YAP is knocked down, there is a decrease in GBM malignant phenotype, including decreased cell proliferation and colony formation in vitro, and decreased tumour growth in vivo. Finally, we elucidated that YAP mediates GBM chemoresistance by inducing tumour cell stemness, which can be overcome by using the YAP inhibitor verteporfin, increasing GBM susceptibility to TMZ in both sensitive and resistant cell lines. In conclusion, this highlights the importance of YAP in driving GBM cell stemness and chemoresistance, a significant clinical problem, and underscores the potential YAP inhibitors hold as a promising and novel adjuvant or combination therapy in the treatment of chemoresistant GBM.