title: CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma.
abstract: Although 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.
authors: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.|Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Elisa M
authors: EM
authors: Noll
authors: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.|Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Christian
authors: C
authors: Eisen
authors: Department of Pathology, University of Heidelberg, Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Heidelberg, Germany.
authors: Albrecht
authors: A
authors: Stenzinger
authors: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.|Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Elisa
authors: E
authors: Espinet
authors: Department of Pathology, University of Heidelberg, Heidelberg, Germany.
authors: Alexander
authors: A
authors: Muckenhuber
authors: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.
authors: Corinna
authors: C
authors: Klein
authors: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.
authors: Vanessa
authors: V
authors: Vogel
authors: Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
authors: Bernd
authors: B
authors: Klaus
authors: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.|Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Wiebke
authors: W
authors: Nadler
authors: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.
authors: Christoph
authors: C
authors: Rösli
authors: Heidelberg Pharma GmbH, Ladenburg, Germany.
authors: Christian
authors: C
authors: Lutz
authors: Heidelberg Pharma GmbH, Ladenburg, Germany.
authors: Michael
authors: M
authors: Kulke
authors: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.|Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Jan
authors: J
authors: Engelhardt
authors: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.|Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Franziska M
authors: FM
authors: Zickgraf
authors: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Octavio
authors: O
authors: Espinosa
authors: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Matthias
authors: M
authors: Schlesner
authors: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
authors: Xiaoqi
authors: X
authors: Jiang
authors: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
authors: Annette
authors: A
authors: Kopp-Schneider
authors: Department of General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors: Peter
authors: P
authors: Neuhaus
authors: Department of General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors: Marcus
authors: M
authors: Bahra
authors: Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors: Bruno V
authors: BV
authors: Sinn
authors: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute of Pharmacy and Molecular Biotechnology, Bioquant, University of Heidelberg, Heidelberg, Germany.|Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center, Heidelberg, Germany.
authors: Roland
authors: R
authors: Eils
authors: Department of General and Visceral Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors: Nathalia A
authors: NA
authors: Giese
authors: Department of General and Visceral Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors: Thilo
authors: T
authors: Hackert
authors: Department of General and Visceral Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors: Oliver
authors: O
authors: Strobel
authors: Department of General and Visceral Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors: Jens
authors: J
authors: Werner
authors: Department of General and Visceral Surgery, University Hospital Heidelberg, Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors: Markus W
authors: MW
authors: Büchler
authors: Department of Pathology, University of Heidelberg, Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors: Wilko
authors: W
authors: Weichert
authors: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.|Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors: Andreas
authors: A
authors: Trumpp
authors: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.|Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors: Martin R
authors: http://orcid.org/0000-0001-9691-7574
authors: MR
authors: Sprick
mesh_terms: D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D000069439:Dasatinib / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism*; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053564:Keratins, Hair-Specific / Q000378:metabolism*; D053531:Keratins, Type II / Q000378:metabolism*; D008297:Male; D016688:Mice, Inbred NOD; D008875:Middle Aged; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000077297:Pregnane X Receptor; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011987:Receptors, Steroid / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C496487:HNF1A protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C507600:KRT81 protein, human; D053564:Keratins, Hair-Specific; D053531:Keratins, Type II; C000625852:NR1I2 protein, human; C000625853:Nr1i2 protein, mouse; D000077297:Pregnane X Receptor; D047428:Protein Kinase Inhibitors; D011987:Receptors, Steroid; D000069347:Erlotinib Hydrochloride; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D017239:Paclitaxel; D000069439:Dasatinib