DDDR-84. The YAP/TAZ-TEAD axis promotes tumor stem cell functionality and cellular heterogeneity in high-grade gliomas

Abstract High-grade gliomas (HGGs) are among the leading causes of cancer-related deaths due to a lack of effective treatments. Common genetic mutations observed in these tumors include alterations in receptor tyrosine kinases (RTKs), such as amplification, mutation, and gene fusions. However, directly targeting RTK variants with tyrosine kinase inhibitors yields only partial responses in patients, due in part to the molecular and cellular heterogeneity within these tumors. To address this challenge, we developed experimental model systems that recapitulate inter- and intra-tumoral heterogeneity to facilitate therapeutic discovery. For this purpose, we created human brain organoid-tumor models of HGG. These organoid models provide an improved ex vivo system for examining how the neural microenvironment shapes cellular and molecular heterogeneity among tumor cells over time. We tested these models for responses to small molecule inhibitors and targeted therapies, including approaches aimed at effector pathways that act downstream or in parallel to RTKs. Candidate targets included the YAP and TAZ transcription factors, which cooperate with TEAD co-factors to promote target gene expression, orchestrate stem cell fate decisions, and drive proliferation during neural development. We examined responses in both tumor and non-tumor cells in the neural microenvironment following pharmacological and genetic inhibition of YAP/TAZ-TEAD, using single-cell RNA sequencing and immunofluorescence to visualize cell-specific responses. We found that YAP/TAZ-TEAD function is required for the growth and progression of HGGs with oncogenic RTK variants. Treatment with small molecule inhibitors targeting YAP/TAZ and TEAD reduced proliferation, inhibited HGG cell self-renewal, and induced both differentiation and apoptosis, mimicking the effects of genetic inhibition, while also reducing intra-tumoral transcriptional heterogeneity. Multi-omic profiling of tumor subpopulations resistant to YAP/TAZ-TEAD inhibitors identified additional targets for combination therapies. Preclinical studies in primary HGG cultures and mouse genetic models corroborated these findings and support our ongoing clinical trial of the YAP/TAZ-TEAD inhibitor verteporfin. Together, our results demonstrate that YAP/TAZ-TEAD inhibition represents a promising therapeutic strategy for HGGs.