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@ARTICLE{Noll:130255,
      author       = {E. M. Noll$^*$ and C. Eisen$^*$ and A. Stenzinger and E.
                      Espinet$^*$ and A. Muckenhuber and C. Klein and V. Vogel and
                      B. Klaus and W. Nadler$^*$ and C. Rösli and C. Lutz and M.
                      Kulke and J. Engelhardt$^*$ and F. Zickgraf$^*$ and O.
                      Espinosa$^*$ and M. Schlesner$^*$ and X. Jiang$^*$ and A.
                      Kopp-Schneider$^*$ and P. Neuhaus and M. Bahra and B. V.
                      Sinn and R. Eils$^*$ and N. Giese and T. Hackert and O.
                      Strobel and J. Werner and M. W. Büchler$^*$ and W.
                      Weichert$^*$ and A. Trumpp$^*$ and M. Sprick$^*$},
      title        = {{CYP}3{A}5 mediates basal and acquired therapy resistance
                      in different subtypes of pancreatic ductal adenocarcinoma.},
      journal      = {Nature medicine},
      volume       = {22},
      number       = {3},
      issn         = {1546-170X},
      address      = {New York, NY},
      publisher    = {Nature America Inc.},
      reportid     = {DKFZ-2017-05335},
      pages        = {278 - 287},
      year         = {2016},
      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.},
      keywords     = {Biomarkers, Tumor (NLM Chemicals) / HNF1A protein, human
                      (NLM Chemicals) / HNF4A protein, human (NLM Chemicals) /
                      Hepatocyte Nuclear Factor 1-alpha (NLM Chemicals) /
                      Hepatocyte Nuclear Factor 4 (NLM Chemicals) / KRT81 protein,
                      human (NLM Chemicals) / Keratins, Hair-Specific (NLM
                      Chemicals) / Keratins, Type II (NLM Chemicals) / Protein
                      Kinase Inhibitors (NLM Chemicals) / Receptors, Steroid (NLM
                      Chemicals) / pregnane X receptor (NLM Chemicals) / Erlotinib
                      Hydrochloride (NLM Chemicals) / CYP3A5 protein, human (NLM
                      Chemicals) / Cytochrome P-450 CYP3A (NLM Chemicals) /
                      Paclitaxel (NLM Chemicals) / Dasatinib (NLM Chemicals)},
      cin          = {A010 / V960 / B080 / C060 / L101},
      ddc          = {610},
      cid          = {I:(DE-He78)A010-20160331 / I:(DE-He78)V960-20160331 /
                      I:(DE-He78)B080-20160331 / I:(DE-He78)C060-20160331 /
                      I:(DE-He78)L101-20160331},
      pnm          = {311 - Signalling pathways, cell and tumor biology
                      (POF3-311)},
      pid          = {G:(DE-HGF)POF3-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26855150},
      pmc          = {pmc:PMC4780258},
      doi          = {10.1038/nm.4038},
      url          = {https://inrepo02.dkfz.de/record/130255},
}