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研究生： 鍾為邦
Wei-Pang Chung
論文名稱： FTY720能克服乳癌細胞對HER2標靶治療所產生之抗性
FTY720 overcomes resistance to HER2-targeted therapy in breast cancer
指導教授： 蘇五洲
Wu-Chou Su
張雋曦
Chun Hei Antonio Cheung
學位類別： 博士
Doctor
系所名稱： 醫學院 - 臨床醫學研究所
Institute of Clinical Medicine
論文出版年： 2022
畢業學年度： 110
語文別： 英文
論文頁數： 83
中文關鍵詞： 乳癌 、HER2陽性 、小分子藥物 、單株抗體 、抗性
外文關鍵詞： Breast cancer, HER2 positive, FTY720, trastuzumab, resistance
相關次數： 點閱：52  下載：8 
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    • HER2陽性乳癌患者的預後，雖在HER2標靶藥物問世後獲得顯著改善，但目前除了針對HER2進行拮抗的策略外，卻缺乏其他非針對HER2蛋白的有效標靶治療。於是，本研究進行了FTY720在HER2陽性乳癌細胞的治療探討。FTY720是一種用於治療難治性多發性硬化症的小分子化合物，先前研究證明在幾種類別的乳癌細胞具有細胞層級的治療效應，但在HER2陽性具抗藥性之乳癌細胞卻仍待深入研究。我們的研究結果顯示，就算是HER2陽性乳癌細胞具有PIK3CA此一導致對標靶療法失效的突變，FTY720仍可對這類細胞產生抑制增生和毒殺效應，其有效濃度若以IC50界定則落於7.5至10 µM之間。除此之外，以FTY720治療過後的細胞，經分析後都可以發現細胞凋亡的比例大幅增加，而且在某些細胞株如HCC1954，不僅細胞凋亡增加，連細胞自噬的功能也受到FTY720的抑制。另外，若將HER2單株抗體trastuzumab與FTY720一起使用於原先對trastuzumab具抗性的HER2陽性乳癌細胞株，除了FTY720本身便可能帶來的療效外，更進一步顯示此合併治療能帶來增益的效果。我們運用了HCC1954細胞株所建立的小鼠腫瘤模式，來證實這樣的效果在活體上依然存在。實驗結果顯示，FTY720與trastuzumab的組合的確能明顯地抑制腫瘤的生長，其腫瘤的平均體積都要比單獨使用FTY720或trastuzumab來得小。因此，我們相信FTY720不僅可以克服 HER2陽性乳癌細胞對HER2標靶所產生之抗性，而且根據FTY720合併trastuzumab在細胞實驗與活體動物實驗的結果，均顯示此一合併療法的效益大於單獨使用FTY720或trastuzumab。難能可貴的是，FTY720的成果不單只在這些已知抗性的細胞株，我們還證實了FTY720在CK-MB-1這株具多重抗藥性細胞上仍保有治療的優勢。必須了解的是，CK-MB-1是從經多線治療的乳癌患者身上獲取之抗性細胞，也經實驗證明該群乳癌細胞，對化療或各式標靶藥物都具有一定的抗性。所以，FTY720的未來發展的確值得期待，希望能夠為HER2陽性乳癌患者，帶來除了HER2標靶治療之外的可能替代藥物。

    Even though the prognosis for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer has significantly improved as a result of the development of HER2-directed therapies, there has been no other reliable treatment option available aside from anti-HER2 strategies. This study investigated the effects of FTY720, a small-molecule compound used in the treatment of refractory multiple sclerosis, on trastuzumab-resistant HER2-positive breast cancer cells. Our findings demonstrated that, despite the presence of a PIK3CA mutation, FTY720 was effective in inhibiting the growth of trastuzumab-resistant breast cancer cell lines with an IC50 ranging from 7.5 to 10 µM and was able to overcome trastuzumab resistance by increasing the number of apoptotic events. In some resistant cell lines such as HCC1954, FTY720 could not only increase apoptotic events but also serve as an autophagy inhibitor. Furthermore, the antiproliferative and cytotoxic effects of FTY720 were even enhanced by the addition of trastuzumab in some resistant cell lines. The combination treatment with FTY720 and trastuzumab also showed a significant anti-tumorigenic effect in a HCC1954 xenograft mouse tumor model compared to treatment outcomes from individual drugs. We propose that FTY720 can overcome trastuzumab resistance in patients with HER2-positive breast cancer, with FTY720 plus trastuzumab showing even greater efficacy in vitro and in vivo than these two drugs alone. Not confined to certain types of resistant mechanism, we demonstrated the antiproliferative effects of FTY720 in the CK-MB-1 cell line, which was developed from breast cancer cells exposed to many anti-HER2 regimens and resistant to many novel drugs. FTY720 still showed its therapeutic potential in this cell line. Thus, FTY720 may be considered as a potential therapeutic option in the treatment of patients who have HER2-positive breast cancer.

    摘要 I Abstract in English II 誌謝 III Abbreviation List IX Chapter 1 Introduction 2-6 Overview of HER2-positive breast cancer 2 Possible resistant mechanism to anti-HER2 therapies 2 The small-molecule drug: FTY720 3 The hypothesis about FTY720 in resistant HER2-positive breast cancer 4 Specific aims for the hypothesis 4 Chapter 2 Materials and Methods 8-17 Cell lines, cell culture, and reagents 8 The patient-derived cell line: CK-MB-1 9 Fluorescence in situ hybridization (FISH) of the HER2 gene 10 Sequencing of the PIK3CA gene 10 Screening for major oncogenic alterations in CK-MB-1 cells 11 Antiproliferative activity in vitro 11 In vitro apoptosis analysis 12 Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) 12 The Western blotting 13 Tests for protein stability 14 The evaluation of cytotoxicity in vitro 14 In situ TUNEL tests and a heterotopic xenograft mouse model with HCC1954 cells 15 A heterotopic xenograft mouse model with CK-MB-1 cells 16 Data analysis and statistics 16 Chapter 3 Results 19-29 HER2-positive breast cancer cell lines were characterized and selected to test the efficacy of FTY720 19 FTY720 is effective in trastuzumab-sensitive or trastuzumab-resistant breast cancer cells with or without PIK3CA mutations 20 FTY720 triggers programmed cell death in trastuzumab-resistant breast cancer cells 20 In addition to increasing apoptosis in trastuzumab-resistant breast cancer cells, FTY720 also induces the inhibition of autophagy in certain types of breast cancer cells 22 In the treatment of trastuzumab-resistant HER2-positive breast cancer cells, FTY720 in combined with trastuzumab improves results 24 The combination effect of FTY720 and trastuzumab in a HCC1954 heterotopic xenograft mouse model 25 Characteristics of a multiple drug-resistant HER2-positive cell line: CK-MB-1 27 In vitro efficacy of FTY720 in the multiple drug-resistant CK-MB-1 cell line 28 Chapter 4 Discussion and conclusion 31-37 Chapter 5 References 39-46 Chapter 6 Appendix-Tables 48-49 Chapter 7 Appendix-Figures 51-80 Curriculum Vitae 81-83

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