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000130255 0247_ $$2doi$$a10.1038/nm.4038
000130255 0247_ $$2pmid$$apmid:26855150
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000130255 0247_ $$2ISSN$$a1546-170X
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000130255 1001_ $$0P:(DE-He78)19623ddc45d1abf5fc016bb0d991054b$$aNoll, Elisa Marie$$b0$$eFirst author
000130255 245__ $$aCYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma.
000130255 260__ $$aNew York, NY$$bNature America Inc.$$c2016
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000130255 520__ $$aAlthough subtypes of pancreatic ductal adenocarcinoma (PDAC) have been described, this malignancy is clinically still treated as a single disease. Here we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers--HNF1A and KRT81--that enable stratification of tumors into different subtypes by using immunohistochemistry. Individuals with tumors of these subtypes showed substantial differences in overall survival, and their tumors differed in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or short hairpin RNA (shRNA)-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4, alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and it is highly expressed in several additional malignancies. These findings designate CYP3A5 as a predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance.
000130255 536__ $$0G:(DE-HGF)POF3-311$$a311 - Signalling pathways, cell and tumor biology (POF3-311)$$cPOF3-311$$fPOF III$$x0
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000130255 650_7 $$2NLM Chemicals$$aBiomarkers, Tumor
000130255 650_7 $$2NLM Chemicals$$aHNF1A protein, human
000130255 650_7 $$2NLM Chemicals$$aHNF4A protein, human
000130255 650_7 $$2NLM Chemicals$$aHepatocyte Nuclear Factor 1-alpha
000130255 650_7 $$2NLM Chemicals$$aHepatocyte Nuclear Factor 4
000130255 650_7 $$2NLM Chemicals$$aKRT81 protein, human
000130255 650_7 $$2NLM Chemicals$$aKeratins, Hair-Specific
000130255 650_7 $$2NLM Chemicals$$aKeratins, Type II
000130255 650_7 $$2NLM Chemicals$$aProtein Kinase Inhibitors
000130255 650_7 $$2NLM Chemicals$$aReceptors, Steroid
000130255 650_7 $$2NLM Chemicals$$apregnane X receptor
000130255 650_7 $$0DA87705X9K$$2NLM Chemicals$$aErlotinib Hydrochloride
000130255 650_7 $$0EC 1.14.14.1$$2NLM Chemicals$$aCYP3A5 protein, human
000130255 650_7 $$0EC 1.14.14.1$$2NLM Chemicals$$aCytochrome P-450 CYP3A
000130255 650_7 $$0P88XT4IS4D$$2NLM Chemicals$$aPaclitaxel
000130255 650_7 $$0RBZ1571X5H$$2NLM Chemicals$$aDasatinib
000130255 7001_ $$0P:(DE-HGF)0$$aEisen, Christian$$b1
000130255 7001_ $$aStenzinger, Albrecht$$b2
000130255 7001_ $$0P:(DE-HGF)0$$aEspinet, Elisa$$b3
000130255 7001_ $$aMuckenhuber, Alexander$$b4
000130255 7001_ $$0P:(DE-HGF)0$$aKlein, Corinna$$b5
000130255 7001_ $$0P:(DE-HGF)0$$aVogel, Vanessa$$b6
000130255 7001_ $$aKlaus, Bernd$$b7
000130255 7001_ $$0P:(DE-He78)067d470839d964b72671ab5d5e2d5a70$$aNadler, Wiebke$$b8
000130255 7001_ $$aRösli, Christoph$$b9
000130255 7001_ $$aLutz, Christian$$b10
000130255 7001_ $$aKulke, Michael$$b11
000130255 7001_ $$0P:(DE-HGF)0$$aEngelhardt, Jan$$b12
000130255 7001_ $$0P:(DE-He78)3fad0b8e145d744f85057abba1fdd0f3$$aZickgraf, Franziska$$b13
000130255 7001_ $$0P:(DE-He78)3a3c8f74863a10048a7c322e73e0740e$$aEspinosa, Octavio$$b14
000130255 7001_ $$0P:(DE-He78)f2a782242acf94a3114d75c45dc75b37$$aSchlesner, Matthias$$b15
000130255 7001_ $$0P:(DE-He78)079436c5442874052d541943e53145ef$$aJiang, Xiaoqi$$b16
000130255 7001_ $$0P:(DE-He78)bb6a7a70f976eb8df1769944bf913596$$aKopp-Schneider, Annette$$b17
000130255 7001_ $$aNeuhaus, Peter$$b18
000130255 7001_ $$aBahra, Marcus$$b19
000130255 7001_ $$aSinn, Bruno V$$b20
000130255 7001_ $$0P:(DE-He78)78b6aa82148e60b4d91e3a37a6d3d9a0$$aEils, Roland$$b21
000130255 7001_ $$0P:(DE-He78)ee6ac6f077e7f03250a3c17e3184a9f9$$aGiese, Nathalia$$b22
000130255 7001_ $$aHackert, Thilo$$b23
000130255 7001_ $$aStrobel, Oliver$$b24
000130255 7001_ $$aWerner, Jens$$b25
000130255 7001_ $$0P:(DE-HGF)0$$aBüchler, Markus W$$b26
000130255 7001_ $$0P:(DE-HGF)0$$aWeichert, Wilko$$b27
000130255 7001_ $$0P:(DE-He78)732f4fbcddb0042251aa759a2e74d3b2$$aTrumpp, Andreas$$b28$$eLast author
000130255 7001_ $$0P:(DE-He78)0f44fcb0b05507b0a20b175f7ba9ed1c$$aSprick, Martin$$b29$$eLast author$$udkfz
000130255 773__ $$0PERI:(DE-600)1484517-9$$a10.1038/nm.4038$$gVol. 22, no. 3, p. 278 - 287$$n3$$p278 - 287$$tNature medicine$$v22$$x1546-170X$$y2016
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