Abstract A144: Sensitization of docetaxel-resistant breast cancer cells to docetaxel by the VRAC modulator SCO-101

Abstract

Abstract Introduction: Breast cancer is the most frequent cancer among women worldwide, and the aggressive subtype triple-negative breast cancer (TNBC) comprises 15% of breast cancer cases. Taxanes are a key component of the (neo)adjuvant treatment for TNBC; however, taxane resistance develops in one in five neoadjuvant or adjuvant taxane-treated patients. Resistance to anticancer drugs represents the main cause of cancer-related deaths. Thus, resensitization of taxane-resistant cancer cells constitutes a highly unmet medical need. Materials and Methods: SCO-101 is a modulator of the Volume Regulated Anion Channel (VRAC) complex. It is an oral drug and has previously passed 4 phase I clinical trials where it demonstrated excellent PK (T1/2=15 hours) and only limited toxicity. In this study we used an isogenic pair of parental (sensitive) and docetaxel (taxane)-resistant MDA-MB-231 human TNBC cells (Hansen et al.,Tumor Biol 2015:36:4327-38). Cell viability in vitro during 72h or 120h exposure to SCO-101 and/or docetaxel was addressed by MTT and Presto blue assays and cell counting. Potential targets for SCO-101 were investigated by transient knockdown of LRRC8a (obligatory component of VRAC) followed by cell viability assay, and by studying Pgp-mediated substrate efflux. Results: In parental MDA-MB-231 cells, SCO-101 and docetaxel each had a dose-dependent effect on cell viability and no combinatorial effects were observed between the drugs. When exposing docetaxel-resistant cells to the combination of SCO-101 and docetaxel, a significant inhibitory effect on cell viability compared to either drug alone was observed, suggesting an additive or synergistic effect between these two drugs with SCO-101 resensitizing the resistant cells to docetaxel. By knockdown of LRRC8a no differences in the response to SCO-101 and/or docetaxel were observed, suggesting that the anticancer effects of SCO-101 are not dependent on this obligatory VRAC component. Alternatively, preliminary experimental interrogation of the Pgp drug efflux pump suggests that SCO-101 affects this well-known docetaxel resistance mechanism. Conclusion and Future Perspectives: These preclinical studies demonstrate that SCO-101 sensitizes docetaxel-resistant breast cancer cells to docetaxel through a mechanism not dependent on LRRC8a expression. Currently, xenotransplant models of mice are being established to examine the in vivo inhibitory effects of SCO-101 on tumor growth. Additionally, we are preparing a clinical phase II study enrolling metastatic TNBC patients who have failed prior docetaxel treatment. These patients will be reexposed to the combination of docetaxel and SCO-101. End-point will be objective response rate according to RECIST 1.1. Citation Format: Sofie O. Bagger, Jørgen Drejer, Nils Brünner, Signe L. Nielsen, Palle Christoffersen, Jan Stenvang. Sensitization of docetaxel-resistant breast cancer cells to docetaxel by the VRAC modulator SCO-101 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A144.