Increased expression of cytochrome P450 3A4 in pancreatic neuroendocrine tumor cells promotes drug resistance

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Introduction: Pancreatic neuroendocrine tumors (PNETs) are slow growing, but often metastasize to the liver. Several systemic treatment options are available for metastatic PNETs but unfortunately fail to improve survival. Hence a better understanding of PNET biology and new therapies are required. In an attempt to identify new drugs for metastatic PNETs, our group performed gene expression analysis of primary PNETs and PNETs that metastasized to lymph nodes and/or liver and identified genes and drug candidates that could potentially help treat metastatic PNETs.

Aim(s): Our goal is to use gene expression data of primary and metastatic PNETs to identify potential drug resistance mechanism(s).

Materials and methods: We identified a general mechanism of drug resistance by which the liver microenvironment promotes PNETs to overexpress cytochrome P450 genes essential for inactivation of many anti-cancer drugs. In particular, the cytochrome P450 CYP3A4 gene is increased by 100-fold in PNETs that metastasize to the liver (validated using an additional 16 patient tumor samples; p < 0.0001). We confirmed the increase of CYP3A4 protein levels in PNET cells by immune-fluorescence in pair-matched PNET primary tumors and liver metastases. We detected an increase expression of cytochrome P450 genes in PNET cells grown in conditioned media from liver cancer cells (Hep G2). We generated BON cells with CYP3A4 knockdown using specific shRNA and observed that cells with decreased CYP3A4 are more sensitive to etoposide, a known substrate of CYP3A4.

Conference: 18th Annual ENETS Concerence (2021)

Presenting Author: Tran C

Authors: Tran C, Li G, Sherman S, Howe J, Ear P,

Keywords: PNET, metastases, drug resistance, liver microenvironment, etoposide, CYP3A4,