Dataset Information

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.

SUBMITTER: Noll EM

PROVIDER: S-EPMC4780258 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Noll Elisa M EM Eisen Christian C Stenzinger Albrecht A Espinet Elisa E Muckenhuber Alexander A Klein Corinna C Vogel Vanessa V Klaus Bernd B Nadler Wiebke W Rösli Christoph C Lutz Christian C Kulke Michael M Engelhardt Jan J Zickgraf Franziska M FM Espinosa Octavio O Schlesner Matthias M Jiang Xiaoqi X Kopp-Schneider Annette A Neuhaus Peter P Bahra Marcus M Sinn Bruno V BV Eils Roland R Giese Nathalia A NA Hackert Thilo T Strobel Oliver O Werner Jens J Büchler Markus W MW Weichert Wilko W Trumpp Andreas A Sprick Martin R MR

Nature medicine 20160208 3

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 sub ...[more]

PMID: 26855150

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Project description:Comprehensive characterization of signaling in pancreatic ductal adenocarcinoma (PDAC) promises to enhance our understanding of the molecular aberrations driving this devastating disease, and may identify novel therapeutic targets as well as biomarkers that enable stratification of patients for optimal therapy. Here, we use immunoaffinity-coupled high-resolution mass spectrometry to characterize global tyrosine phosphorylation patterns across two large panels of human PDAC cell lines: the ATCC series (19 cell lines) and TKCC series (17 cell lines). This resulted in the identification and quantification of over 1800 class 1 tyrosine phosphorylation sites and the consistent segregation of both PDAC cell line series into three subtypes with distinct tyrosine phosphorylation profiles. Subtype-selective signaling networks were characterized by identification of subtype-enriched phosphosites together with pathway and network analyses. This revealed that the three subtypes characteristic of the ATCC series were associated with perturbations in signaling networks associated with cell-cell adhesion and epithelial-mesenchyme transition, mRNA metabolism, and receptor tyrosine kinase (RTK) signaling, respectively. Specifically, the third subtype exhibited enhanced tyrosine phosphorylation of multiple RTKs including the EGFR, ERBB3 and MET. Interestingly, a similar RTK-enriched subtype was identified in the TKCC series, and 'classifier' sites for each series identified using Random Forest models were able to predict the subtypes of the alternate series with high accuracy, highlighting the conservation of the three subtypes across the two series. Finally, RTK-enriched cell lines from both series exhibited enhanced sensitivity to the small molecule EGFR inhibitor erlotinib, indicating that their phosphosignature may provide a predictive biomarker for response to this targeted therapy. These studies highlight how resolution of subtype-selective signaling networks can provide a novel taxonomy for particular cancers, and provide insights into PDAC biology that can be exploited for improved patient management.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in the world with a five-year survival rate of less than 5%. Not all PDAC are the same, because there exist intra-tumoral heterogeneity between PDAC, which poses a great challenge to personalized treatments for PDAC.MethodsTo dissect the molecular heterogeneity of PDAC, we performed a retrospective meta-analysis on whole transcriptome data from more than 1200 PDAC patients. Subtypes were identified based on non-negative matrix factorization (NMF) biclustering method. We used the gene set enrichment analysis (GSEA) and survival analysis to conduct the molecular and clinical characterization of the identified subtypes, respectively.ResultsSix molecular and clinical distinct subtypes of PDAC: L1-L6, are identified and grouped into tumor-specific (L1, L2 and L6) and stroma-specific subtypes (L3, L4 and L5). For tumor-specific subtypes, L1 (~?22%) has enriched carbohydrate metabolism-related gene sets and has intermediate survival. L2 (~?22%) has the worst clinical outcomes, and is enriched for cell proliferation-related gene sets. About 23% patients can be classified into L6, which leads to intermediate survival and is enriched for lipid and protein metabolism-related gene sets. Stroma-specific subtypes may contain high non-epithelial contents such as collagen, immune and islet cells, respectively. For instance, L3 (~?12%) has poor survival and is enriched for collagen-associated gene sets. L4 (~?14%) is enriched for various immune-related gene sets and has relatively good survival. And L5 (~?7%) has good clinical outcomes and is enriched for neurotransmitter and insulin secretion related gene sets. In the meantime, we identified 160 subtype-specific markers and built a deep learning-based classifier for PDAC. We also applied our classification system on validation datasets and observed much similar molecular and clinical characteristics between subtypes.ConclusionsOur study is the largest cohort of PDAC gene expression profiles investigated so far, which greatly increased the statistical power and provided more robust results. We identified six molecular and clinical distinct subtypes to describe a more complete picture of the PDAC heterogeneity. The 160 subtype-specific markers and a deep learning based classification system may be used to better stratify PDAC patients for personalized treatments.

Dataset Information

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

Publications

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

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