- 學位論文
糖尿病對肺癌治療的影響：對於手術治療的肺癌病患術後影響及標靶藥物在肺癌細胞的影響
The Impact of Diabetes on Lung Cancer Treatment: Postoperative Outcomes in Lung Cancer Patients and EGFR-TKI Treatment of Lung Cancer Cells
摘要
糖尿病對早期肺癌患者，接受肺癌切除手術的術後影響，以及糖尿病對於肺癌晚期病患，使用表皮生長因子酪胺酸激酶抑製劑（EGFR-TKI）的療效影響，仍存在爭議。我們在肺癌病患的世代研究中，調查肺癌病患同時合併糖尿病， 是否會造成較高風險的術後併發症或死亡率。我們還研究高胰島素血症與高血糖，在體外非小細胞肺癌細胞（HCC4006細胞株，具有表皮生長因子受體突變特性），是否影響吉非替尼（gefitinib）的治療效果。 本世代研究有 25,456 名接受肺切除手術的肺癌患者。我們將原本有糖尿病的患者與沒有糖尿病的患者按 1:1 做傾向評分匹配。結果在 8234 名傾向評分匹配的肺癌病人中，有糖尿病的患者，其器官/空間手術部位感染（勝算比：1.67；95%信賴區間：1.01 至 2.78；p = 0.04）、肺炎（勝算比：1.24；95%信賴區間：1.03 至 1.48；p = 0.02），心肌梗塞（勝算比：1.87；95%信賴區間：1.10 至 3.18；p = 0.02）的風險顯著高於對照組。因此，我們建議外科醫生採取預防措施，以盡量減少術後併發症，尤其是對於風險較高的糖尿病早期肺癌手術患者。 在體外試驗，我們使用增生測試(MTS proliferation assay)和西方點墨分析(Western blotting)，以及通過轉染小分子干擾核糖核酸 (siRNA transfection)，來評估吉非替尼(gefitinib)、長效胰島素(glargine)或合併兩種藥物(gefitinib 加glargine)的治療療效，以及對細胞增殖及 EGFR、IGFR、AKT 和 ERK 在細胞內蛋白表現量的影響。結果發現，高胰島素血症會促進肺癌細胞的增殖和存活，並降低吉非替尼(gefitinib)的療效。高胰島素血症抑制吉非替尼(gefitinib)功效可能是通過磷酸肌醇 3 激酶 (PI3K/AKT) 途徑，而不是絲裂原活化蛋白激酶細胞外信號調節激酶 (MAPK/ERK) 途徑介導的。此外，siRNA對AKT（絲胺酸/蘇胺酸激酶）的抑制作用，可以回復高胰島素血症造成的吉非替尼(gefitinib)藥效降低。本研究發現：高胰島素血症會降低吉非替尼(gefitinib)在EGFR突變的肺癌細胞的治療效果。然而還需要其他研究證實，例如共同靶向治療或抑制PI3K / AKT途徑的藥物，應用於晚期糖尿病肺癌病人，希望得以改善晚期肺癌且同時有糖尿病的病患在使用EGFR-TKI的療效。
並列摘要
The impact of diabetes mellitus (DM) on postoperative outcomes in early-stage lung cancer patients undergoing pulmonary resections and the efficacy of epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI) therapy for advanced lung cancer remains controversial. We investigated whether pre-existing DM is associated with higher risks of postoperative morbidity and mortality in a lung cancer population-based cohort. We also investigated the roles of hyperinsulinemia and hyperglycemia in mediating gefitinib efficacy in NSCLC cells with activating EGFR mutations in vitro. We identified 25,456 lung cancer patients who underwent elective pulmonary resections. Patients with pre-existing DM were propensity score-matched at 1:1 with those without DM. Among 8234 propensity score-matched adults, the risks of organ/space surgical site infection (OR: 1.67; 95% CI: 1.01 to 2.78; p = 0.04), pneumonia (OR: 1.24; 95% CI: 1.03 to 1.48; p = 0.02), and myocardial infarction (MI; OR: 1.87; 95% CI: 1.10 to 3.18; p = 0.02) were significantly higher in the DM group than in the control group. Hence, we recommend that thoracic surgeons take precautions to minimize postoperative complications, especially for high-risk patients with DM. In vitro, the effects of gefitinib, glargine, and both drugs on cell proliferation, and intracellular expression levels of EGFR, IGFR, AKT, and ERK on HCC 4006 cells were examined using an MTS proliferation assay, western blot analysis, and transfection of siRNAs. The results showed that hyperinsulinemia upregulated cell proliferation and survival, and reduced gefitinib efficacy. Hyperinsulinemia suppressing gefitinib efficacy may be mediated via the phosphoinositide 3 kinase (PI3K/AKT) pathway rather than the mitogen-activated protein kinase extracellular signal-regulated kinase (MAPK/ERK) pathway. AKT serine/threonine kinase knockdown by siRNA could recover the gefitinib efficacy that was induced by hyperinsulinemia. In conclusion, hyperinsulinemia was identified to suppress gefitinib efficacy in NSCLC cells with activating EGFR mutations. However, additional studies are required to investigate strategies, such as co-targeting hyperinsulinemia and the PI3K/AKT pathway, to recover EGFR TKI efficacy in patients with NSCLC.