<p>Transcription factor motifs with high similarity to the TAZ binding motif (related to Figure 4).</p>
Funding
NIH
NINDS
American Brain Tumor Association Discovery Grant
United States Department of Defense
NHGRI grant
ARTICLE ABSTRACT
Hyperactivated EGFR signaling is a driver of various human cancers, including glioblastoma (GBM). Effective EGFR-targeted therapies rely on knowledge of key signaling hubs that transfer and amplify EGFR signaling. Here we focus on the transcription factor TAZ, a potential signaling hub in the EGFR signaling network. TAZ expression was positively associated with EGFR expression in clinical GBM specimens. In patient-derived GBM neurospheres, EGF induced TAZ through EGFR–ERK and EGFR–STAT3 signaling, and the constitutively active EGFRvIII mutation caused EGF-independent hyperactivation of TAZ. Genome-wide analysis showed that the EGFR–TAZ axis activates multiple oncogenic signaling mechanisms, including an EGFR–TAZ–RTK positive feedback loop, as well as upregulating HIF1α and other oncogenic genes. TAZ hyperactivation in GBM stem-like cells induced exogenous mitogen-independent growth and promoted GBM invasion, radioresistance, and tumorigenicity. Screening a panel of brain-penetrating EGFR inhibitors identified osimertinib as the most potent inhibitor of the EGFR–TAZ signaling axis. Systemic osimertinib treatment inhibited the EGFR–TAZ axis and in vivo growth of GBM stem-like cell xenografts. Overall these results show that the therapeutic efficacy of osimertinib relies on effective TAZ inhibition, thus identifying TAZ as a potential biomarker of osimertinib sensitivity.
This study establishes a genome-wide map of EGFR–TAZ signaling in glioblastoma and finds osimertinib effectively inhibits this signaling, justifying its future clinical evaluation to treat glioblastoma and other cancers with EGFR/TAZ hyperactivation.
