Abstract
Resistance to kinase inhibitors and paclitaxel depends on CYP3A5 expression in exocrine-like PDAC cells.
Major finding: Resistance to kinase inhibitors and paclitaxel depends on CYP3A5 expression in exocrine-like PDAC cells.
Concept: HNF1A and KRT81 biomarkers stratify PDAC subtypes and are associated with differential prognosis.
Impact: CYP3A5 levels predict resistance to certain PDAC therapies, and its inhibition may prevent resistance.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with chemotherapies offering only limited benefit. Poor patient response to existing therapies has been attributed to inadequate in vivo models and unknown molecular mechanisms of resistance. To address these limitations, Noll, Eisen, and colleagues established patient-derived primary xenografts, matched primary PDAC cell lines (PACO), and PACO cell–derived tumors from each of the three subtypes, classic, quasi-mesenchymal (QM-PDA), and exocrine-like. Candidate biomarkers were selected based on subtype-specific gene expression, and restricted staining of hepatocyte nuclear factor 1α (HNF1A) and cytokeratin 81 (KRT81) was sufficient to stratify patients into three PDAC subtypes, revealing significant differences in overall survival in retrospective studies. Treatment of PACO cell lines with the tyrosine kinase inhibitors erlotinib or dasatinib or the chemotherapeutic agent paclitaxel revealed selective drug resistance in exocrine-like cells. Inhibition of the CYP family enzymes, which metabolize small molecules via oxidation, re-sensitized exocrine-like PACO cells to kinase inhibitor and paclitaxel treatment. Expression of cytochrome P450 3A5 (CYP3A5), but not CYP3A4 or CYP3A7, was high in exocrine-like PACO cells and HNF1A+ patient samples, and was further induced upon drug treatment. In line with this finding, shRNA-mediated suppression of CYP3A5 resensitized exocrine-like PDAC cells to erlotinib, dasatinib, and paclitaxel in vitro and in preclinical patient-derived xenografts. Depletion of transcription factors upstream of CYP3A5 revealed that high basal levels of CYP3A5 were dependent on expression of HNF4A, whereas induction of CYP3A5 in response to drug treatment was dependent on the nuclear receptor NR1I2. Extended suppression of CYP3A5 also resensitized exocrine-like cells in vivo, without the development of resistance. Furthermore, upon longer-term treatment CYP3A5 levels were upregulated and conferred acquired drug resistance in QM-PDA and classic PDAC cell lines as well as other tumor types. Together, these data suggest that upregulation of CYP3A5 contributes to drug resistance in PDAC and may represent a broad mechanism of resistance in cancer.
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