【佳學基因檢測】DNA依賴性蛋白激酶在介導常染色體顯性多囊腎病囊腫生長中的作用

腫瘤基因檢測需要多長時間香港

根據(jù)認識到《Int J Mol Sci》在?2021 Sep 29;22(19):10512發(fā)表了一篇題目為《DNA依賴性蛋白激酶在介導常染色體顯性多囊腎病囊腫生長中的作用》腫瘤靶向藥物治療基因檢測臨床研究文章。該研究由Ashley N Chandra?,?Sayanthooran Saravanabavan?,?Gopala K Rangan??等完成。促進了腫瘤的正確治療與個性化用藥的發(fā)展，進一步強調了基因信息檢測與分析的重要性。

腫瘤靶向藥物及正確治療臨床研究內(nèi)容關鍵詞：

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腫瘤靶向治療基因檢測臨床應用結果

DNA 依賴性蛋白激酶 (DNA-PK) 是一種參與 DNA 損傷反應 (DDR) 信號傳導的絲氨酸/蘇氨酸蛋白，由于其對增殖和存活的多效性作用，可能介導常染色體顯性多囊腎病 (ADPKD) 中的腎囊腫生長。為了驗證這一假設，評估了人 ADPKD 中 DNA-PK 的表達以及在 Madin-Darby 犬腎 (MDCK) 囊腫生長和人 ADPKD 細胞的三維模型中 DNA-PK 抑制的體外效果。在人類 ADPKD 中，DNA-PK 復合物的所有三個亞基的 mRNA 表達增加，并且使用免疫組織化學，在人類 ADPKD 的囊腫襯里上皮細胞中以局灶方式檢測到催化亞基 (DNA-PKcs)。在體外，經(jīng)過 6-12 天的長期治療，NU7441（一種 DNA-PK 激酶抑制劑）可將 MDCK 囊腫的生長減少多達 52%。盡管與正常人腎細胞 (HK-2) 相比，人 ADPKD 細胞系 (WT9-7/WT9-12) 對 DNA-PK 激酶抑制的反應沒有表現(xiàn)出合成殺傷力，但低劑量 NU7441 的組合增強了抗西羅莫司對 WT9-7 和 WT9-12 細胞的增殖作用分別為 17 ± 10% 和 11 ± 7%。總之，這些初步數(shù)據(jù)表明，DNA-PK 在沒有綜合致死相互作用的情況下介導體內(nèi)腎囊腫生長，從而在人類 ADPKD 細胞中賦予細胞特異性。 NU7441 增強了雷帕霉素復合物 1 抑制劑的抗增殖作用，但作用不大。

腫瘤發(fā)生與反復轉移國際數(shù)據(jù)庫描述：

DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein involved in DNA damage response (DDR) signaling that may mediate kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD) due to its pleiotropic effects on proliferation and survival. To test this hypothesis, the expression of DNA-PK in human ADPKD and the in vitro effects of DNA-PK inhibition in a three-dimensional model of Madin-Darby Canine Kidney (MDCK) cyst growth and human ADPKD cells were assessed. In human ADPKD, the mRNA expression for all three subunits of the DNA-PK complex was increased, and using immunohistochemistry, the catalytic subunit (DNA-PKcs) was detected in the cyst lining epithelia of human ADPKD, in a focal manner. In vitro, NU7441 (a DNA-PK kinase inhibitor) reduced MDCK cyst growth by up to 52% after long-term treatment over 6-12 days. Although human ADPKD cell lines (WT9-7/WT9-12) did not exhibit synthetic lethality in response to DNA-PK kinase inhibition compared to normal human kidney cells (HK-2), the combination of low-dose NU7441 enhanced the anti-proliferative effects of sirolimus in WT9-7 and WT9-12 cells by 17 ± 10% and 11 ± 7%, respectively. In conclusion, these preliminary data suggest that DNA-PK mediates kidney cyst growth in vivo without a synthetically lethal interaction, conferring cell-specificity in human ADPKD cells. NU7441 enhanced the anti-proliferative effects of rapamycin complex 1 inhibitors, but the effect was modest.