YAP/TAZ transcriptional co-activators create therapeutic vulnerability to verteporfin in EGFR mutant glioblastoma

Purpose Glioblastoma (GBM), neoplasms derived from glia and neuro-glial progenitor cells, are the most common and lethal malignant primary brain tumors diagnosed in adults, with a median survival of 14 months. GBM tumorigenicity is often driven by genetic aberrations in receptor tyrosine kinases (RTKs), such as amplification and mutation of EGFR. Experimental design Using a Drosophila glioma model and human patient-derived GBM stem cells and xenograft models, we genetically and pharmacologically tested whether the YAP and TAZ transcription co-activators, effectors of the Hippo pathway that promote gene expression via TEAD co-factors, are key drivers of GBM tumorigenicity downstream of oncogenic EGFR signaling. Results YAP and TAZ are highly expressed in EGFR-amplified/mutant human GBMs, and their knockdown in EGFR-amplified/mutant GBM cells inhibited proliferation and elicited apoptosis. Our results indicate that YAP/TAZ-TEAD directly regulate transcription of SOX2, C-MYC, and EGFR itself to create a feedforward loop to drive survival and proliferation of human GBM cells. Moreover, the benzoporphyrin derivative verteporfin, a disruptor of YAP/TAZ-TEAD mediated transcription, preferentially induced apoptosis of cultured patient-derived EGFR-amplified/mutant GBM cells, suppressed expression of YAP/TAZ transcriptional targets, including EGFR, and conferred significant survival benefit in an orthotopic xenograft GBM model. Our efforts led us to design and initiate a phase 0 clinical trial of Visudyne, an FDA-approved liposomal formulation of verteporfin, where we used intraoperative fluorescence to observe verteporfin uptake into tumor cells in GBM tumors in human patients. Conclusions Together, our data suggest that verteporfin is a promising therapeutic agent for EGFR amplified and mutant GBM.