- 學位論文
KRAS/BRAF突變之大腸直腸癌患者可能的治療策略
The Possible Therapeutic Strategy for Colorectal Cancer with KRAS/BRAF Mutations
摘要
大腸直腸癌在台灣為最好發之惡性腫瘤之一,其發生率每年約有一萬人。許多研究指出藉由阻斷訊息傳遞路徑可抑制細胞異常增生。而標靶藥物爾必德舒(Cetuximab)為一表皮生長因子類似物,其証實能與表皮生長因子受體(EGFR)結合,進而抑制細胞增生使患者存活率增加。但爾必德舒使用在轉移性大腸直腸癌個案中若具有EGFR下游基因-Kirsten ras (KRAS)和v-raf murine sarcoma viral oncogene homolog B1 (BRAF) 的突變存在,其治療效果明顯不彰。2011年有研究指出微小核糖核酸-378 在 KRAS 突變型 與野生型基因中其表現量具有意義之差異性。而此微小核糖核-378 乃是具有調控 MAPK 途徑調控因子之一。據此,我們假設此微小核糖核酸-378 能調控 MAPK活化路徑,使將近50%KRAS或 BRAF突變之大腸直腸癌患者可提升標靶藥物治療效果。本篇以七株大腸直腸癌細胞株進行基因突變型態歸納做為實驗模型,觀察微小核糖核酸-378與標靶藥物反應敏感度之彼此相關性。實驗結果指出（一）KRAS或BRAF突變與否與微小核醣核酸-378表現量有高度相關性。（二）轉染微小核醣核酸-378後再添加標靶藥物,發現對所有突變型態細胞有效增加其對標靶藥物敏感性。（三）藉由微小核醣核酸-378 表現量 提升造成腫瘤細胞增生現象,間接証實 KRAS 與 BRAF 突變型大腸癌其實存在有不同 的潛在腫瘤發展機轉。研究結論,微小核糖核酸-378 的高表達對於提高標靶藥物作用性提供具體成果,未來可能成為在近五成的 KRAS 或 BRAF 突變之大腸直腸癌患者無 效治療上,重燃一新的治療契機。
並列摘要
Colorectal cancer (CRC) is the most common human malignancies in Taiwan, with incidences of 10 thousand people per year. A number of studies suggested that blocking abnormal cell proliferation by inhibiting the MAPK(mitogen-activated protein kinase) pathway could be a promising treatment method for CRC. Target drug “cetuximab”, an epidermal growth factor (EGF) competitor which inhibit cell proliferation has been shown to improve the survival rate. Earlier reports indicated that mutations in the genes such as KRAS and BRAF which are downstream of the EGFR lead to the deleterious activation MAPK pathway regardless of the EGFR antibody (Cetuximab) treatment. A previous report in 2011, down regulation of miR-378 was identified in CRC patients, who possesses KRAS mutations. miR-378 as one of the regulators of MAPK pathway. Herein, we aimed to compare expression levels of miR-378 in wild type and mutated CRC cell lines and further to study the role of miR-378 in Cetuximab responses. We used seven cell lines as experiment models. Our results indicated 1. The significant differences in expression of miR-378 when compare with KRAS or BRAF mutated cell and wild type cells. Further, 2. after transfected miR-378 to both the mutated and wild type cell lines, we found expression of miR-378 did increase cetuximab response rates as expected. 3. Base on the rate of cell proliferation that after transfected miR-378, the different mechanisms of tumor development could be revealed. Our findings might contribute to the development of a possible therapeutic strategy to block multiple oncogenes for near 50% of colorectal cancers contain with KRAS or BRAF mutations.