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| 題名: | 探討小分子藥物BMS-345541在肺腺癌作為新型 EGFR/ErbB2酪胺酸激酶抑制劑的效應
Studying the effects of BMS-345541, a small molecule drug, as a tyrosine-kinase inhibitor of EGFR/ErbB2 in lung adenocarcinoma. |
| 作者: | 程馨嫺
CHENG, HSING-HSIEN |
| 貢獻者: | 醫學科學研究所碩士班
鄭嘉雄 |
| 關鍵詞: | BMS-345541;酪胺酸激酶抑制劑;非小細胞肺癌;EGFR;ErbB2
BMS-345541;TKI;NSCLC;EGFR;ErbB2 |
| 日期: | 2021-07-02 |
| 上傳時間: | 2022-03-16 23:07:11 (UTC+8) |
| 摘要: | 惡性腫瘤的形成概括多種因素和複雜地演變過程，近十年，肺癌在死亡原因之惡性腫瘤排名中位居前三名，而非小細胞肺癌為肺癌最常見類型。目前已經有針對非小細胞肺癌的抗癌藥物可以使用，但治療後產生的抗藥性是造成病人癒後存活率下降的原因。因此，新型抗癌藥物的開發，尤其是表皮生長因子受體EGFR (epidermal growth factor receptor) 酪胺酸激酶抑制劑 (tyrosine kinase inhibitor, TKI) 一直都是相當重要的研究主題。NF-κB在正常組織擔任重要的調節角色，一旦調控失常，則與癌症、炎自、體免疫、病毒以及免疫發育異常等有關。EGFR參與多種腫瘤的生長和惡化過程，包括刺激細胞生長、爬行、血管新生、細胞週期和凋亡等，因此是潛在的生物標誌物，可作為診斷、預後和治療工具。BMS-345541為高度選擇性的抑制IKK-α與IKK-β活性的小分子藥物，因此，本研究將探討BMS-345541抑制肺腺癌進程的可能機制。本研究結果表明，經由BMS-345541處理PC9及H441肺腺癌細胞株，明顯抑制癌細胞的生長，但IκBα的磷酸化並未受到抑制，顯示BMS-345541具有新的抑制癌細胞生長的功能。通過RNA Sequencing (RNA-Seq) 分析得知BMS-345541在PC9細胞抑制與DNA replication信號途徑相關的基因表現，以Ingenuity Pathway Analysis (IPA)分析調控基因表現的上游訊息路徑，發現與EGFR/ErbB2的訊息路徑有關。BMS-345541可以明顯的抑制PC9及H441細胞中EGFR與ErbB2的磷酸化，下游的Akt、mTOR的磷酸也明顯的受到抑制。而ERK1/2的磷酸化在PC9細胞中受到抑制，但在Ras基因突變的H441細胞中則沒有影響。在RNA-Seq分析中受到BMS-345541抑制的RRM2和TK1基因，其蛋白表現量也明顯的到抑制。因此，推論在非小細胞肺癌中，BMS-345541可作為新型EGFR / ErbB2酪胺酸激酶抑制劑的功能。
The development of cancer is a multistep process. In the decade, lung cancer has been top three causes of cancer death. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Many anti-cancer drugs have been developed for treatment of NSCLC. However, drug-resistance decreased overall survival rate of NSCLC patients. It’s needed to develop novel anticancer drugs, especially the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for NSCLC. NF-κB plays an important regulatory role in normal tissues. Once the regulation is abnormal, it may lead to cancer, inflammation, autoimmunity, viruses, and immune development abnormalities. The role of EGFR regulates various tumor-promoting process of cancers, including cell growth, migration, angiogenesis, cell cycle progression, and cell apoptosis. Therefore, EGFR is a potential diagnostic, prognostic and therapeutic biomarkers. BMS-345541 is a small molecule drug for highly selective inhibition of IKK-α and IKK-β activities. This subject investigated the function of BMS-345541 on inhibition of NSCLC process. We found that BMS-345541 inhibited growth of adenocarcinoma PC9 and H441 cell lines without reducing phosphorylation of IκBα. It suggested that a novel and unknown function of BMS-345541 on inhibition of NSCLC. RNA sequencing (RNA-Seq) analysis showed that BMS-345541 inhibited gene expression related to DNA replication in PC9 cells. Analyzing the upstream-regulative signaling of reduction genes by Ingenuity Pathway Analysis (IPA) showed that EGFR/ErbB2 signaling might be a possible candidate. Further, the phosphorylation levels of Akt and mTOR in PC9 and H441 cells were significantly reduced by BMS-345541. The phosphorylation of ERK1/2 were decreased by BMS-345541 in PC9 cells but not in H441 cells, which was contained RAS mutation. The protein levels of downstream RRM2 and TK1 was also lower in PC9 and H441 cells. Collectively, our results suggested a novel function of BMS-34554 as a TKI in NSCLC. |
| 描述: | 碩士
指導教授：鄭嘉雄
委員：陳顧中
委員：張茂山 |
| 資料類型: | thesis |
| 顯示於類別: | [醫學科學研究所] 博碩士論文
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