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CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma

Nature Medicine volume 22, pages 278–287 (2016)Cite this article

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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.

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Figure 1: Subtype stratification of PDAC models and patients by using two markers.
Figure 2: Exocrine-like PDAC cells, which express CYP3A5, are resistant to TKIs.
Figure 3: CYP3A5 mediates drug resistance and is regulated by HNF4A and NR1I2 expression in exocrine-like PDAC cells in vitro.
Figure 4: CYP3A5 mediates drug resistance in exocrine-like PDAC cells in vivo.
Figure 5: CYP3A5 contributes to acquired resistance in QM-PDA and classical PDAC cells.
Figure 6: CYP3A5 contributes to drug resistance in other malignancies.

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Acknowledgements

We thank E. Soyka, S. Bauer and A. Hieronymus for excellent technical assistance. We also thank the microarray and the next-generation sequencing (NGS) unit of the Genomics and Proteomics Core Facility, DKFZ, for providing expression profiling, NGS and related services, and all members of the flow cytometry core facility for excellent support. We thank DKFZ-HIPO for technical support and funding through grant no. HIPO-015 (M.S., R.E., N.A.G., O.S., T.H., A.T. and M.R.S.). This work was supported in part by the Dietmar Hopp Foundation and the BioRN Spitzencluster 'Molecular- and Cell-based Medicine' (E.M.N., C.E., E.E., C.K., V.V., W.N., C.R., J.E., F.M.Z., A.T. and M.R.S.), the German Bundesministerium für Bildung und Forschung (BMBF) e:Med program for systems biology (PANC-STRAT consortium, grant no. 01ZX1305; A.T., M.R.S., M.S., R.E., N.A.G., T.H., O.S., A.S., A.M. and W.W.), the Helmholtz Preclinical Comprehensive Cancer Center (E.E., A.T. and M.R.S.) and the DKFZ-NCT program NCT3.0 (A.T., M.R.S., O.E., M.S., R.E., N.A.G., T.H. and O.S.). A.S. was supported by a fellowship from the NCT–Heidelberg School of Oncology (HSO). E.E. is recipient of an EMBO long-term fellowship (ALTF 344-2013). The collection and processing of the specimens via PancoBank was supported by Heidelberger Stiftung Chirurgie (M.W.B.), BMBF (grant no. 01GS08114; M.W.B.) and Biomaterial Bank Heidelberg–BMBH (BMBF grant no. 01EY1101; A.S. and W.W.).

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Author notes

  1. Albrecht Stenzinger, Alexander Muckenhuber, Christoph Rösli, Jens Werner & Wilko Weichert

    Present address: Present addresses: Department of Pathology, Center for Integrated Diagnostics (CID), Massachusetts General Hospital, Boston, Massachusetts, USA (A.S.); Institute of Pathology, Technical University Munich (TUM), Munich, Germany (A.M. and W.W.); Sandoz Biopharmaceuticals, Oberhaching, Germany (C.R.); Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians University, Munich, Germany (J.W.).,

  2. Elisa M Noll and Christian Eisen: These authors contributed equally to this work.

  3. Andreas Trumpp and Martin R Sprick: These authors jointly directed this work.

Authors and Affiliations

  1. Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany

    Elisa M Noll, Christian Eisen, Elisa Espinet, Corinna Klein, Vanessa Vogel, Wiebke Nadler, Christoph Rösli, Jan Engelhardt, Franziska M Zickgraf, Andreas Trumpp & Martin R Sprick

  2. Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Elisa M Noll, Christian Eisen, Elisa Espinet, Wiebke Nadler, Jan Engelhardt, Franziska M Zickgraf, Andreas Trumpp & Martin R Sprick

  3. Department of Pathology, University of Heidelberg, Heidelberg, Germany

    Albrecht Stenzinger, Alexander Muckenhuber & Wilko Weichert

  4. National Center for Tumor Diseases (NCT), Heidelberg, Germany

    Albrecht Stenzinger & Wilko Weichert

  5. Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany

    Bernd Klaus

  6. Heidelberg Pharma GmbH, Ladenburg, Germany

    Christian Lutz & Michael Kulke

  7. Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Octavio Espinosa, Matthias Schlesner & Roland Eils

  8. Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany

    Xiaoqi Jiang & Annette Kopp-Schneider

  9. Department of General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Peter Neuhaus & Marcus Bahra

  10. Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Bruno V Sinn

  11. Institute of Pharmacy and Molecular Biotechnology, Bioquant, University of Heidelberg, Heidelberg, Germany

    Roland Eils

  12. Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center, Heidelberg, Germany

    Roland Eils

  13. Department of General and Visceral Surgery, University Hospital Heidelberg, Heidelberg, Germany

    Nathalia A Giese, Thilo Hackert, Oliver Strobel, Jens Werner & Markus W Büchler

  14. German Cancer Consortium (DKTK), Heidelberg, Germany

    Markus W Büchler, Wilko Weichert, Andreas Trumpp & Martin R Sprick

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Contributions

E.M.N. and C.E. share first authorship, and A.S. and E.E. share second authorship of this paper. E.M.N. and C.E. established, conducted and analyzed the experiments; A.S., A.M. and W.W. performed immunohistological analyses of all of the tissue specimens presented and performed respective data analyses; E.E. did the immunofluorescence staining experiments and analyses on publicly available data sets; B.K., W.N. and C.R. performed RNA expression analyses on the PDAC validation cohort; C.K., V.V., J.E., F.M.Z., O.E., M.S. and R.E. provided technical and experimental support; C.L. and M.K. conducted and analyzed LC-MS/MS experiments; X.J. and A.K.-S. performed activity area calculations; P.N., M.B. and B.V.S. provided PDAC tissue microarray characterization; N.A.G., T.H., O.S., J.W. and M.W.B. provided samples of individuals with PDAC; A.T. and M.R.S. supervised the project; E.N., C.E., A.T. and M.R.S. developed the concept, designed experimental studies, analyzed the data and wrote the manuscript.

Corresponding authors

Correspondence to Andreas Trumpp or Martin R Sprick.

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Noll, E., Eisen, C., Stenzinger, A. et al. CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma. Nat Med 22, 278–287 (2016). https://doi.org/10.1038/nm.4038

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