TY - JOUR
T1 - Egfr activates a taz-driven oncogenic program in glioblastoma
AU - Gao, Minling
AU - Fu, Yi
AU - Zhou, Weiqiang
AU - Gui, Gege
AU - Lal, Bachuchu
AU - Li, Yunqing
AU - Xia, Shuli
AU - Ji, Hongkai
AU - Eberhart, Charles G.
AU - Laterra, John
AU - Ying, Mingyao
N1 - Funding Information:
This work was supported by grants from the NIH/NINDS R01NS099460 R21NS106407 R21NS101400 (to M. Ying), 5R01NS110087 5R01NS096754 (to J. Laterra), the American Brain Tumor Association Discovery Grant (to M. Ying), and the Career Development Award from the United States Department of Defense (W81XWH-14-1-0176 to M. Ying). W. Zhou and H. Ji were partially supported by the NIH/NHGRI grant R01HG009518. The authors thank Dr. Angelo Vescovi and Dr. Ichiro Nakano for providing human GBM cell models.
Funding Information:
W. Zhou reports grants from NIH/NHGRI during the conduct of the study. H. Ji reports grants from NIH during the conduct of the study. M. Ying reports grants from NINDS, American Brain Tumor Association and CDMRP from the United States Department of Defense during the conduct of the study. No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - 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 HIF1a and other oncogenic genes. TAZ hyperactivation in GBM stemlike 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.
AB - 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 HIF1a and other oncogenic genes. TAZ hyperactivation in GBM stemlike 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.
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U2 - 10.1158/0008-5472.CAN-20-2773
DO - 10.1158/0008-5472.CAN-20-2773
M3 - Article
C2 - 33910930
AN - SCOPUS:85109041602
SN - 0008-5472
VL - 81
SP - 3580
EP - 3592
JO - Cancer Research
JF - Cancer Research
IS - 13
ER -