BAK is a predictive and prognostic biomarker for the therapeutic effect of docetaxel treatment in patients with advanced gastric cancer
BAK is a predictive and prognostic biomarker for the therapeutic effect of docetaxel treatment in patients with advanced gastric cancer
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DOI：
10.1007/s10120-015-0557-1
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发表时间：
2016-07-01
期刊：
影响因子：
7.4
通讯作者：
Kato, Junji
中科院分区：
文献类型：
--
作者：
Kubo, Tomohiro;Kawano, Yutaka;Kato, Junji
术前化疗是晚期胃癌根治术前降低分期的一种有希望的策略，尽管可能发生严重的不良事件，临床结果往往不令人满意。为了确定药物敏感性的预测性生物标志物，我们使用了精心设计的功能性细胞凋亡试验，并评估了化疗敏感性与临床结果之间的相关性。研究了11株胃癌细胞株对多西紫杉醇、顺铂和5-氟尿嘧啶的药物敏感性。进行bcl2 -同源结构域3 （BH3）分析并评估其与药物敏感性的相关性。术前化疗前对临床胃癌标本进行免疫组化染色，评估其与组织病理反应及临床转归的相关性。BIM (BCL2L11)-BH3分析结果与多西紫杉醇敏感性和BAK蛋白表达相关，BAK蛋白敲低导致多西紫杉醇耐药。通过对69例胃癌标本术前化疗（包括多西紫杉醇治疗）前BAK表达指数的数值相乘，描述BAK阳性程度和观察到的染色强度。标本显示良好的化疗组织病理学反应的患者比克指数高于反应较差的患者。BAK指数为千分之一日元3的患者无进展生存期（HR, 2.664; 95% CI, 1.352-5.248; P = 0.005）和总生存期（HR, 3.390; 95% CI, 1.549-7.422; P = 0.002）得到改善。BH3分析清楚地表明BIM的表达与多西他赛的敏感性相关，而BIM的表达依赖于BAK的表达。因此，BAK在胃癌中的表达可预测术前化疗患者对多西紫杉醇的化疗反应和临床预后。
Preoperative chemotherapy is a promising strategy for downstaging advanced gastric cancer before radical resection, although severe adverse events can occur and clinical outcomes are often unsatisfactory. To identify predictive biomarkers of drug sensitivity, we used a well-designed functional apoptosis assay and assessed the correlations between chemosensitivity and clinical outcomes.Drug sensitivity to docetaxel, cisplatin, and 5-fluorouracil was examined in 11 gastric cancer cell lines. BCL2-homology domain 3 (BH3) profiling was performed and assessed for correlations with drug sensitivity. Immunohistochemical staining of clinical gastric cancer specimens was performed before preoperative chemotherapy, and correlations with histopathological responses and clinical outcomes were assessed.BIM (BCL2L11)-BH3 profiling results correlated with docetaxel sensitivity and BAK protein expression, whose knockdown caused docetaxel resistance. The BAK expression indexes of 69 gastric cancer specimens before preoperative chemotherapy (including docetaxel treatment) were determined by multiplying numerical values describing the degrees of BAK positivity and staining intensity observed. Patients whose specimens showed good chemotherapeutic histopathological responses had higher BAK indexes than those with poor responses. Patients with BAK index values a parts per thousand yen3 showed improved progression-free survival (HR, 2.664; 95 % CI, 1.352-5.248; P = 0.005) and overall survival (HR, 3.390; 95 % CI, 1.549-7.422; P = 0.002).BH3 profiling clearly showed that BIM expression, which depends on BAK expression, correlated with docetaxel sensitivity. BAK expression in gastric cancer is thus predictive of chemotherapeutic responses to docetaxel and clinical prognosis in patients treated with preoperative chemotherapy.