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

Abstract

Although subtypes of pancreatic ductal adenocarcinoma (PDAC) were 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 immunohistochemistry. Individuals bearing tumors of these subtypes show significant differences in overall survival and their tumors differ 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 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 is highly expressed in several additional malignancies. These findings designate CYP3A5 as predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance.

Tumor Heterogeneity in Pancreatic Adenocarcinoma

“…To date, no correlation has been established between these subtypes and any histological feature, except for the squamous signature that is more frequent in adenosquamous carcinomas. Noll et al [32] proposed that the classification of Collisson et al [29] could be recapitulated by immunochemistry by assessing the expression of HNF1A and KRT81. This requires external validation and no subtype is currently assigned to double-positive tumors, but it may represent an interesting tool to subtype tumors and could have a major clinical impact.…”

Concepts to Target MYC in Pancreatic Cancer

“…The squamous subtype of the disease, which overlaps with the quasi-mesenchymal subtype defined by Collisson and colleagues (21), is characterized by an activated MYC pathway (20) and the poorest outcome (20)(21)(22). These observations moreover reinforce MYC being a relevant driver in PDAC and argue that MYC targeting strategies are needed.…”

Barcelona conference on epigenetics and cancer 2016 – beyond cancer genomes

“…37 As part of his presentation, Dr. Trumpp focused on different models for pancreatic ductal adenocarcinoma, including PDX models and primary cell lines derived thereof. He indicated that inhibition of metabolic enzyme cytochrome P450 3A5 (CYP3A5) influences tumor sensitivity to genotoxic drugs and targeted tyrosine kinase inhibitors, 38 thus unveiling CYP3A5 as a new potential target with respect to therapy resistance to clinically used drugs.…”