EGFR Activates a TAZ-Driven Oncogenic Program in Glioblastoma
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 28, 2021
- Source ID
- 10.1158/0008-5472.can-20-2773
Entities
People
- Bachuchu Lal
- Charles G. Eberhart
- Gege Gui
- Hongkai Ji
- John Laterra
- Mingyao Ying
- Minling Gao
- Shuli Xia
- Weiqiang Zhou
- Yi Fu
- Yunqing Li
Organizations
- American Brain Tumor Association
- Johns Hopkins Bloomberg School of Public Health
- Johns Hopkins University
- National Institute of Neurological Disorders and Stroke
- National Institutes of Health
- United States Department of Defense