Frank Szulzewsky, Investigator at Huntsman Cancer Institute, shared a post on LinkedIn:
“I’m so excited to share our new preprint, the first manuscript that originated entirely from my own lab at the University of Utah School of Medicine and Huntsman Cancer Institute.
Thank you to Dylan Keiser and Meghan Buddy and all the collaborators at HCI and the Department of Neurosurgery.
YAP1/TAZ-TEAD signaling is a central signaling hub in meningioma, however, the efficacy of TEAD inhibition against meningioma cells has not extensively been studied. Using established and patient-derived meningioma cell lines, we demonstrate that genetic ablation of YAP1/TAZ suppresses growth in both NF2 mutant and NF2 wild type cell lines, establishing YAP1/TAZ-TEAD signaling as a shared oncogenic dependency.
Pharmacologic TEAD inhibition suppressed growth of benign NF2 mutant and a subset of higher-grade NF2 mutant meningiomas, whereas NF2 wild type meningiomas were generally more resistant. RNA-Seq and Western Blot analysis identified compensatory activation of MEK-ERK, mTOR-S6, and FAK signaling in resistant lines exhibit.
Importantly, co-targeting these pathways was able to overcome resistance to TEADi and was superior to MEK/mTOR/FAK inhibition alone. These studies provide a compelling proof-of-concept that TEADi represents a novel therapeutic vulnerability in meningioma and reveal adaptive signaling responses that can be therapeutically exploited.”
Title: Comprehensive analysis of TEAD inhibition in meningioma identifies MEK and mTOR inhibition as effective combination therapies against resistant lines.
Authors: Dylan J. Keiser, Meghan S. Buddy, Solmaz Mojarad-Jabali, Qing Li, Missia Kohler-Skinner, David Gillespie, David Nix, Howard Colman, William Couldwell, Randy Jensen, Frank Szulzewsky
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