Abstract C68: SLCO1B3 influences taxane-response in prostate cancer

Introduction: Castration resistant prostate cancer (CRPC) patients are treated with docetaxel as first-line chemotherapy. Unfortunately, response to docetaxel is highly variable among patients and intrinsic or acquired resistance is common. Understanding mechanisms of resistance may help to define biomarkers to select patients for the best therapy options and prevent treatments to which they may respond poorly. We established docetaxel-resistant xenografts from chemotherapy-naive patient-derived xenografts (PDXs) in vivo . Next generation sequencing analysis of these chemotherapy-naive and docetaxel-resistant PDXs revealed that SLCO1B3 expression was significantly downregulated in a subset of docetaxel-resistant tumors. As SLCO1B3 is also a known transporter of testosterone, the aim of the study was to further investigated its expression in relation with hormonal status of CRPC cells. Methods: Androgen responsive SLCO1B3 expressing PC346C cells were used to perform uptake assays with [ 14 C]-labeled docetaxel and cabazitaxel after silencing of SLCO1B3 with siRNA. The androgen resistant PC346C-DCC-G clone, created by long-term culturing of PC346C cells in androgen deprived medium, did not express SLCO1B3. PC346C-DCC-G cells were stably transfected with SLCO1B3 or with a control construct containing green fluorescent protein (GFP). MTT cell proliferation assays were performed after 10 days of exposure to docetaxel or cabazitaxel in a dose range of 0-10nM. Prostate specific antigen (PSA) production was measured with an ELISA assay after exposure of 0.1nM testosterone for 30 minutes. Results: Silencing of SLCO1B3 in parental PC346C decreased uptake of docetaxel and cabazitaxel 2.0-fold (p = 0.01) and 2.1-fold (p = 0.0003), respectively. In line with this observation, SLCO1B3-transfected, overexpressing PC346C-DCC-G cells were more sensitive to docetaxel and cabazitaxel, resulting in reduced IC50-values of 1.9-fold for docetaxel and 3.5-fold for cabazitaxel compared to control transfected cells. Moreover, PSA production in SLCO1B3-overexpressing PC346C-DCC-G cells increased 2-fold as compared to control (p = 0.05) after testosterone exposure. Conclusion: Prostate cancer cells that overexpress SLCO1B3 are more sensitive to docetaxel and cabazitaxel treatment, which could be linked to increased uptake of both taxanes. Further studies are needed to clarify the role of SLCO1B3 in the uptake of cabazitaxel into the cell. Moreover, SLCO1B3 expression affects hormonal status of prostate cancer cells as reflected by PSA production. Research is ongoing to further elucidate the role of SLCO1B3 in prostate cancer and its impact on taxane efficacy and response. Citation Format: Ellen S. de Morree, Rene Bottcher, Robert J. van Soest, Ashraf Aghai, Corrina M. de Ridder, Alice A. Gibson, Ron HJ Mathijssen, Herman Burger, Erik AC Wiemer, Alex Sparreboom, Wytske M. van Weerden, Ronald de Wit. SLCO1B3 influences taxane-response in prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C68.