Loss of SLCO1B3 drives taxane resistance in prostate cancer

Abstract

Background:Both taxanes, docetaxel and cabazitaxel, are effective treatments for metastatic castration-resistant prostate cancer (mCRPC). However, resistance to taxanes is common. Our objective was to investigate mechanisms of taxane resistance in prostate cancer.Methods:Two docetaxel-resistant patient-derived xenografts (PDXs) of CRPC were established (PC339-DOC and PC346C-DOC) in male athymic nude mice by frequent intraperitoneal administrations of docetaxel. Next-generation sequencing was performed on PDX tissue pre- and post-docetaxel resistance and gene expression profiles were compared. [14C]-docetaxel and [14C]-cabazitaxel uptake assays in vitro and cytotoxicity assays were performed to validate direct involvement of transporter genes in taxane sensitivity.Results:Organic anion-transporting polypeptide (SLCO1B3), an influx transporter of docetaxel, was significantly downregulated in PC346C-DOC tumours. In accordance with this finding, intratumoural concentrations of docetaxel and cabazitaxel were significantly decreased in PC346C-DOC as compared with levels in chemotherapy-naive PC346C tumours. In addition, silencing of SLCO1B3 in chemo-naive PC346C resulted in a two-fold decrease in intracellular concentrations of both taxanes. Overexpression of SLCO1B3 showed higher sensitivity to docetaxel and cabazitaxel.Conclusions:The SLCO1B3 determines intracellular concentrations of docetaxel and cabazitaxel and consequently influences taxane efficacy. Loss of the drug transporter SLCO1B3 may drive taxane resistance in prostate cancer.

ABCB1 Mediates Cabazitaxel–Docetaxel Cross-Resistance in Advanced Prostate Cancer

“…The mechanisms of resistance to docetaxel have been investigated and shown to include loss of p53 functioning, increased expression of β-tubulin isoforms, decreased expression of BRCA1, and increased expression of the drug efflux pump ABCB1 (10–12). Mechanisms of cabazitaxel resistance are lesser known but are thought to include the presence of the retinoblastoma protein and loss of the membrane transporter SLCO1B3 (13, 14). Whether there exists cross-resistance between docetaxel and cabazitaxel is poorly understood.…”

Identification of synergistic drug combinations using breast cancer patient-derived xenografts

“…Both EGFR and BIRC5 are highly expressed in basallike PDXs, cell lines, and patients, and high expression of both genes reduces metastasis-free survival, suggesting that co-targeting of these proteins holds promise for potential clinical success in TNBC. therefore suitable models for studying tumor biology and drug response, both in vivo and ex vivo/in vitro [22][23][24][25][26][27][28][29][30][31][32][33][34][35] . Using this approach, we have generated a dataset that can be used to quickly assess and compare responses of breast cancer PDXs of varying subtypes to many different drugs, most of which are approved by the U.S. Food and Drug Administration (FDA) for various cancer or non-cancer indications.…”

Association between SLCO1B3 gene polymorphism and prostate cancer risk: A meta-analytic study

“…It is mainly responsible for transporting endogenous and exogenous substances to hepatocyte for metabolism (Ayalasomayajula et al, 2016). OATP1B3 is a liver-specific transporter (de Morree et al, 2016). It is generally localized in liver cell membrane in sinusoid side (Bedewy and El-Maghraby, 2013).…”

“…It is found in recent studies that, high OATP1B3 expression exists in tumor tissues and cells like prostate cancer, colon cancer and lung cancer. SLCO1B3 shows obvious gene polymorphism (de Morree et al, 2016). Notably, 334T>G and 699G>A haplotypes can markedly affect the transport activity of OATP1B3 (Bedewy and ElMaghraby, 2013;Suga et al, 2017).…”