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 EGFindependent 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.

CXCR4 expression is associated with proneural‐to‐mesenchymal transition in glioblastoma

“…Recently, it was shown that EGFR-driven TAZ activation lead to increased CXCR4 expression in patient-derived GBM oncospheres. 39 In the present study, we found that tumors with higher CXCR4 expression had higher expression of both the CEBP/STAT3 and TAZ regulons. These findings indicate that increased CXCR4 expression is a common mechanism of distinct upstream regulators of PMT and suggests that CXCR4 signaling could be a therapeutic target that neutralizes redundant signaling mechanisms in PMT.…”

Signaling pathways in brain tumors and therapeutic interventions

“… 366 – 368 EGFR amplification EGFRvIII mutation (deletion of exons 2–7) The Ras/Mek/Erk Signaling The PI3K/AKT/mTOR Signaling The STAT3/5 Signaling The mTORC2/NF-κB Signaling The Notch Signaling In GBM, 40–50% of the genes were amplified, including half of these genes with EGFRvIII mutation, and 10–20% of genes were overexpressed without amplification The 27% of IDH-wt LGG, does not exist in IDH-mut LGG Potential therapeutic targets. 84 , 86 , 90 , 93 , 96 , 369 – 374 PTEN mutations/deletions The PI3K/AKT/mTOR Signaling The sonic hedgehog signaling The 41% of GBM The 23% of IDH-wt LGG, not exist in IDH-mut LGG Poor prognosis. Potential therapeutic targets.…”

Algorithmic reconstruction of glioblastoma network complexity

“…The following reference appears in the Supplemental Information: Amson et al., 2013 ; Azim et al., 2009 ; Baritaki et al., 2009 ; Bhaduri et al., 2020 ; Bhat et al., 2011 ; Brozzi et al., 2009 ; Bulstrode et al., 2017 ; de la Rocha et al., 2014 ; Ehmsen et al., 2013 ; Engel et al., 2020 ; Gao et al., 2021 ; Grimm et al., 2020 ; Gu et al., 2014 ; Hagiwara, 2011 ; Harroch et al., 2002 ; Hou et al., 2016 ; Hoxha et al., 2020 ; Koziol et al., 2007 ; Liu et al., 2013 ; Lü et al., 2020 ; Luxen et al., 2017 ; Mani et al., 2008 ; Miao et al., 2019 ; Polisetty et al., 2012 ; Roy et al., 2020 ; Saito et al., 2007 ; Shi et al., 2017 ; Tao et al., 2020 ; Thompson et al., 2009 ; Wang et al., 2013 , 2015 ; Yamasaki et al., 2001 ; Yu et al., 2020 .…”