Background Hepatitis B virus infection was identified as the main risk factor of hepatocellular carcinoma (HCC) in China, which induced a high morbidity and mortality. In recent years, circRNAs were reported involving in the oncogenesis and development of multiple malignant tumors. Method Bioinformatical analysis has been employed to predict the relevant circRNA with AHNAK. The loss of function and gain of function have been used by knocking‐down circRNA through the shRNA technology while overexpressing through lentivirus infection. Dual‐luciferase reporter assay was used to detect circRNA binding to miRNA and target genes. We further used immunoprecipitation technique to detect the binding ability between non‐coding RNAs. Results In this study, according to the previous report, we mainly focused on AHNAK, which has been confirmed as an oncogene involving in the metastasis of HCC. Bioinformatics analysis showed that circ_0008194 could be spliced by AHNAK. In this study, the abnormal upregulated circ_0008194 in tumor tissues was detected. The positive correlation between circ_0008194 and AHNAK was also confirmed. Through knockdown and overexpression of circ_0008194, we conducted in vitro functional studies. We found circ_0008194 could induce the invasion of cells in vitro. Mechanically, circ_0008194 presented the binding ability with miR‐190a causing the suppression of miR‐190a expression, causing the competitive inhibition of AHNAK, resulting in the promotion of EMT. Conclusion Our results suggested that circ_0008194 may act as a sponge to adsorb miR‐190a, thereby promoting the expression of AHNAK and promoting the metastasis of liver cancer tumors.
Tarloxotinib (TRLX) is a prodrug that releases an irreversible EGFR/HER2 tyrosine kinase inhibitor (TRLX-TKI) under pathophysiologically hypoxic conditions. Non-small cell lung cancer (NSCLC) has been characterized as a hypoxic disease and approximately 15% of lung adenocarcinomas harbor EGFR mutations. While most EGFR mutations predict for response to several FDA-approved tyrosine kinase inhibitors, in-frame insertions in exon 20 of EGFR are activating mutations in the tyrosine kinase domain that have significantly decreased sensitivity to EGFR inhibitors and currently have no approved targeted therapies. We derived and characterized three human lung adenocarcinoma cell lines with different EGFR exon 20 insertions in order to accelerate development of targeted therapies for this mutation class. Using these novel cell lines, we evaluated tarloxotinib as a therapeutic agent for tumors harboring this type of mutations. We demonstrate that our three patient-derived cell lines: CUTO14 (p.A767_V769dupASV), CUTO17 (p.N771_H773dupNPH), and CUTO18 (p.S768_770dupSVD) are dependent on EGFR for cell proliferation using shRNA-mediated knockdown. Our results show that EGFR exon 20 insertion cell lines are resistant to gefitinib; however, treatment with afatinib or TRLX-TKI reduces cell proliferation and signaling in a similar manner. The IC50 values for the three cell lines were 203nM, 89nM, and 709 nM for afatinib and 208nM, 33nM, and 345nM for TRLX-TKI, respectively. The prodrug form of tarloxitinib has minimal effect on cell proliferation in these models, consistent with the necessity for hypoxia-induced activation (to TRLX-TKI). Importantly, we evaluated the effect of tarloxotinib in vivo using murine xenograft models of CUTO14 and CUTO17. After four weeks of treatment, afatinib did not alter tumor growth compared to untreated tumors, whereas treatment with tarloxotinib induced significant tumor regression. The in vivo data suggest that the activated TKI of tarloxitinib is accumulating to biologically active concentrations in tumors following cleavage of tarlxoxotinib under hypoxic conditions. We conclude that our EGFR exon 20 insertions cell lines represent novel models for the investigation of therapeutic strategies for this mutation class. These cell lines have the ability to develop tumors in vivo and show reduced sensitivity to current EGFR TKIs, mimicking the lack of response in patients with these mutations. Finally, we demonstrate that tarloxotinib can overcome intrinsic EGFR exon 20 mutation resistance to standard EGFR TKIs. Citation Format: Adriana Estrada-Bernal, Andrea E. Doak, Anh T. Le, Hengbo Zhu, Nan Chen, Shevan Silva, Jeff B. Smaill, Adam V. Patterson, Robert C. Doebele. Antitumor activity of tarloxotinib, a hypoxia-activated EGFR TKI, in patient-derived lung cancer cell lines harboring EGFR exon 20 insertions [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A157.
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