激活性的表皮生長因子受體（EGFR）突變，啟動癌化的發生，並且也促進腫瘤針對突變EGFR的EGFR酪氨酸激酶抑製劑（TKIs）效果增加。 SOX2在肺前驅細胞中決定細胞命運決定因子的作用。然而，SOX2表達如何影響TKI治療和肺癌中的腫瘤侵襲尚未了解。在這篇研究中我們報導了突變的EGFR與SOX2相互作用以維持肺癌細胞的增殖，其中一些通過關閉SOX2表達來產生癌細胞異質性，由此促進TKI抗性和侵襲性。通過shRNA對SOX2誘導的上皮 - 間質轉化（EMT）下調SOX2表達並賦予細胞對TKI的抗性。 TKI的治療能夠篩選出具有EMT並且SOX2低表達的EGFR突變肺癌細胞。相反的，增強內源性SOX2表達可逆轉EMT並增加對TKIs的敏感性。免疫組織化學分析顯示低SOX2表達能夠在帶有EGFR突變的患者中預測較差的存活。綜上所述，我們的研究結果顯示了透過表觀遺傳介導的SOX2表達和TKI選擇引發的癌症可塑性如何產生不同的癌細胞異質性和TKI敏感性，並且也為EGFR突變的肺癌腫瘤進展提供了重要見解。

Activating mutations in the epidermal growth factor receptor (EGFR), while initiating lung tumorigenesis, render tumors susceptible to EGFR-tyrosine kinase inhibitors (TKIs). SOX2 functions as a cell fate determination factor in lung progenitor cells. However, how SOX2 expression affects TKI treatment and tumor invasion in lung cancer is obscure. Here we report that EGFR mutations crosstalk with SOX2 to maintain cell proliferation and dissemination in lung cancer cells, some of which generate heterogeneity by switching off SOX2 expression, thus promoting TKI resistance and invasiveness. Downregulation of SOX2 expression by shRNA against SOX2 induced epithelial-to-mesenchymal transition (EMT) and endowed cell resistant to TKIs. TKI treatment selected EGFR-mutated lung cancer cells harboring low SOX2 expression with the EMT signature. Conversely, enhancing endogenous SOX2 expression reverses EMT and increases sensitivity to TKIs. Immunohistochemistry analysis revealed that low SOX2 expression predicts a poor survival in patients harboring EGFR mutations. Taken together, our findings show how cancer plasticity elicited by epigenetically mediated SOX2 expression and TKI selection generates distinct oncogenic properties and TKI sensitivity, providing critical insights into tumor progression in EGFR-mutated lung cancer.

Abstract …….……………………………………………….…….………………2
Acknowledgement ………………………………………………………………5
Introduction .……………………………………………..……………..7
Materials and methods ………………………………………….12
Results .…………………………………………………….…………………….17
Discussion .…………………………………………………………………….23
Figures .…………………………………………………………………………..29
Reference ……………………………………………….……………………….47

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