CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma.
CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma.
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DOI：
10.1038/nm.4038
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发表时间：
2016-03
期刊：
影响因子：
82.9
通讯作者：
Sprick MR
中科院分区：
文献类型：
--
作者：
Noll EM;Eisen C;Stenzinger A;Espinet E;Muckenhuber A;Klein C;Vogel V;Klaus B;Nadler W;Rösli C;Lutz C;Kulke M;Engelhardt J;Zickgraf FM;Espinosa O;Schlesner M;Jiang X;Kopp-Schneider A;Neuhaus P;Bahra M;Sinn BV;Eils R;Giese NA;Hackert T;Strobel O;Werner J;Büchler MW;Weichert W;Trumpp A;Sprick MR
虽然胰腺导管腺癌(PDAC)的亚型已被描述，但这种恶性肿瘤在临床上仍被视为一个单独的疾病。在这里，我们提供了患者来源的模型，代表了以前发现的准间充质(QM-PDA)、经典和外分泌样PDAC亚型的全谱，并识别了两个标记物-HNF1A和KRT81-通过免疫组织化学将肿瘤分层为不同的亚型。携带这些亚型肿瘤的个体在总体存活率方面有显著差异，他们的肿瘤对药物敏感性也不同，外分泌样亚型对酪氨酸激酶抑制剂和紫杉醇具有耐药性。细胞色素P450 3A5(CYP3A5)在外分泌样亚型的肿瘤中代谢这些化合物，药物或shRNA介导的CYP3A5抑制使肿瘤细胞对这些药物敏感。肝细胞核因子4α(HNF4a)控制细胞色素P3A5的基础表达，而药物诱导的细胞色素P3A5上调是由核受体NR1I2介导的。CYP3A5在QM-PDA和经典PDAC中也与获得性耐药有关，并在其他几种恶性肿瘤中高表达。这些发现表明，CYP3A5是治疗反应的预测因子，是一种必须克服的肿瘤细胞自主解毒机制，以防止耐药。
Although subtypes of pancreatic ductal adenocarcinoma (PDAC) were described, this malignancy is clinically still treated as a single disease. Here, we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers—HNF1A and KRT81—that enable stratification of tumors into different subtypes by immunohistochemistry. Individuals bearing tumors of these subtypes show significant differences in overall survival and their tumors differ in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or shRNA-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4 alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and is highly expressed in several additional malignancies. These findings designate CYP3A5 as predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance.