Journal Article

DKFZ-2017-05335

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma.

Noll, E. M. (First author)DKFZ* ; Eisen, C.DKFZ* ; Stenzinger, A. ; Espinet, E.DKFZ* ; Muckenhuber, A. ; Klein, C. ; Vogel, V. ; Klaus, B. ; Nadler, W.DKFZ* ; Rösli, C. ; Lutz, C. ; Kulke, M. ; Engelhardt, J.DKFZ* ; Zickgraf, F.DKFZ* ; Espinosa, O.DKFZ* ; Schlesner, M.DKFZ* ; Jiang, X.DKFZ* ; Kopp-Schneider, A.DKFZ* ; Neuhaus, P. ; Bahra, M. ; Sinn, B. V. ; Eils, R.DKFZ* ; Giese, N.Extern* ; Hackert, T. ; Strobel, O. ; Werner, J. ; Büchler, M. W.DKFZ* ; Weichert, W.DKFZ* ; Trumpp, A. (Last author)DKFZ* ; Sprick, M. (Last author)DKFZ*

2016
Nature America Inc. New York, NY

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Please use a persistent id in citations: doi:10.1038/nm.4038

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.

Keyword(s): Biomarkers, Tumor ; HNF1A protein, human ; HNF4A protein, human ; Hepatocyte Nuclear Factor 1-alpha ; Hepatocyte Nuclear Factor 4 ; KRT81 protein, human ; Keratins, Hair-Specific ; Keratins, Type II ; Protein Kinase Inhibitors ; Receptors, Steroid ; pregnane X receptor ; Erlotinib Hydrochloride ; CYP3A5 protein, human ; Cytochrome P-450 CYP3A ; Paclitaxel ; Dasatinib

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Contributing Institute(s):

1. Stammzellen und Krebs (A010)
2. HI-Stem (V960)
3. Theoretische Bioinformatik (B080)
4. Biostatistik (C060)
5. DKTK Heidelberg (L101)

Research Program(s):

1. 311 - Signalling pathways, cell and tumor biology (POF3-311) (POF3-311)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 30 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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