Abstract 4155: Crosstalk of SOX2 and epithelial-to-mesenchymal transition on EGFR-TKI resistance

Abstract

Abstract EGFR-tyrosine kinase inhibitors (TKIs) have been shown to produce profound therapeutic responses in lung adenocarcinoma harboring EGFR mutations. Despite this initial response, patients with EGFR-mutated lung adenocarcinoma ultimately developed resistance to EGFR-TKIs. Although both SOX2 and epithelial-to-mesenchymal (EMT) have been linked to the EGFR-TKI resistance in lung adenocarcinoma, the interplay between SOX2 and EMT in EGFR-TKI resistance is not known. Here, we report that cancer plasticity switched by SOX2 and EMT regulates EGFR-TKI resistance. We found that the selection of EGFR-TKI resistant cells induced EMT while attenuating SOX2 expression. We observed that EGFR-TKI treatment induced SOX2 expression in EGFR-mutated lung cancer cells, and SOX2 silencing encouraged EGFR-TKI resistance. Preselection of EGFR-mutated lung cancer cells with the EMT feature endowed cells with EGFR-TKI resistance but suppressed SOX2 expression. We found that TGF-β induced EMT but attenuated SOX2 expression, resulting in increased EGFR-TKI resistance. Pharmacological inhibition of HDACs in EGFR-mutated cells attenuated SOX2 expression but induced EMT, causing increased EGFR-TKI resistance. Enriching SOX2 expression in EGFR-mutated cells attenuated EMT and rendered cells more sensitive to EGFR-TKIs. Correlation analysis exhibited negative correlations between SOX2 and EMT markers in primary non-small cell lung cancer. Kaplan-Meier analysis revealed that a SOX2 low/Vimentin high signature predicted a poor survival in EGFR-mutated lung adenocarcinoma. Our findings support the notion that the cancer plasticity regulated by SOX2 and EMT plays a critical role in EGFR-TKI resistance, and SOX2 and Vimentin can function as prognostic biomarkers in lung cancer progression. Citation Format: An-Chun Lee, Yu-Fan Chiu, Ming-Han Kuo, Yuan-Hung Wang, Yu-Ting Chou. Crosstalk of SOX2 and epithelial-to-mesenchymal transition on EGFR-TKI resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4155. doi:10.1158/1538-7445.AM2017-4155