Abstract
Comparatively less toxic and more tolerated, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are recommendable for advanced non-small-cell lung cancer (NSCLC) patients with EGFR-sensitive mutations. Some EGFR wild-type patients with specific biomarkers also show a response to the drug. TAZ is an oncogene closely associated with the therapeutic effect of EGFR-TKIs. However, this association remains to be clarified. This study aimed to clarify the mechanism through which TAZ sensitizes EGFR wild-type NSCLC to gefitinib. We used CCK-8 assays and in vivo experiments to investigate the influence of TAZ on gefitinib in EGFR wild-type NSCLC. To further validate the tumorigenic role of TAZ, we performed Human umbilical vein endothelial cell (HUVEC) tube formation and migration assays. Luciferase reporter assays, quantitative real-time PCR (qPCR), immunoblotting and Chromatin immunoprecipitation collaborated with qPCR illuminated the mechanism through which TAZ caused those phenotypes. The results showed TAZ promoted the angiogenesis of NSCLC cell lines and improved gefitinib sensitivity in EGFR wild-type NSCLC in vitro and in vivo. Luciferase reporter assays and ChIP-qPCR experiments showed TAZ upregulated AREG by promoting its transcription. EGFR signaling pathway was activated as TAZ was highly expressed. Rescue experiments were conducted to confirm the indispensable role of AREG in tumorigenesis and gefitinib sensitivity regulated by TAZ. Our study concluded that TAZ sensitized EGFR wild-type NSCLC to gefitinib through promoting amphiregulin transcription.
Highlights
Of all malignancies, lung cancer has the highest morbidity and mortality worldwide[1]
Gefitinib reversibly binds to EGFR tyrosine kinase domain and competitively inhibits ATP binding and downstream phosphorylation, suppressing tumor growth mediated by EGFR signaling pathway[7]
Compared to those in the control group, Human umbilical vein endothelial cell (HUVEC) cultivated in H460-derived medium exhibited a stronger tube-forming capacity that dramatically reduced when these cells further cultivated in A549-derived medium in the absence of TAZ (Fig. 2a, b)
Summary
Lung cancer has the highest morbidity and mortality worldwide[1]. About 85% of lung cancer cases fall victim to non-small-cell lung cancer (NSCLC)[2]. Platinum-based chemotherapy combined with thoracic radiation serves as the standard treatment for advanced NSCLC patients ineligible for surgery[3]. Compared with docetaxel or pemetrexed, epidermal growth factor receptor-tyrosine kinase inhibitors TKIs) present higher tolerability and less toxicity in advanced NSCLC patients with EGFR-sensitive mutations[5]. EGFR-TKI can prolong the progression-free survival of selected patients[6]. Gefitinib is the first targeted drug approved to treat selected NSCLC patients. Gefitinib reversibly binds to EGFR tyrosine kinase domain and competitively inhibits ATP binding and downstream phosphorylation, suppressing tumor growth mediated by EGFR signaling pathway[7]. EGFR-TKIs were proven to be effective as first-line drugs in patients with EGFR-sensitive mutations[3].
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