Abstract 4895: Human ATP-binding cassette proteins ABCB1 and ABCG2 confer resistance to histone deacetylase 6 inhibitor ricolinostat (ACY-1215) in cancer cell lines

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Abstract Histone deacetylase 6 (HDAC6), localized primarily in the cytoplasm, is responsible for the deacetylation of non-histone substrates such as α-tubulin and heat shock protein 90 (Hsp90). HDAC6 has recently emerged as an important epigenetic therapeutic target for cancer, and much effort has been invested into developing novel inhibitors of HDAC6. Ricolinostat (ACY-1215) is the first safe and well tolerated inhibitor of HDAC6 that has progressed into human clinical trials, both as a single agent and in combination therapy. Ricolinostat is currently under evaluation in phase I and II clinical trials in patients with multiple myeloma, relapsed or refractory lymphoid malignancies, relapsed chronic lymphocytic leukemia, unresectable or metastatic breast cancer and for the treatment of gynecological cancer. The overexpression of ATP-binding cassette (ABC) drug transporters ABCB1 and ABCG2 in cancer cells is often associated with the development of multidrug resistance (MDR) phenotype and poor clinical outcome in patients with metastatic breast cancer, chronic lymphocytic leukemia or relapsed multiple myeloma. In this study, we report that ABCB1 and ABCG2 are capable of actively transporting and conferring resistance to ricolinostat. Moreover, we demonstrated that the efficacy of ricolinostat on the activity of HDAC6 and drug-induced apoptosis was significantly reduced in ABCB1- and ABCG2-overexpressing cancer cells, which can be fully restored by an competitive inhibitor of ABCB1 or ABCG2.Our finding is supported by biochemical data and a docking analysis of ricolinostat in the drug-binding pocket of ABCB1 and ABCG2. Taken together, our study indicate that the overexpression ABCB1 or ABCG2 in cancer cells may potentially play a significant role in the development of resistance to ricolinostat in cancer cells. Citation Format: Sung-Han Hsiao, Shahrooz Vahedi, Suresh V. Ambudkar, Chung-Pu Wu. Human ATP-binding cassette proteins ABCB1 and ABCG2 confer resistance to histone deacetylase 6 inhibitor ricolinostat (ACY-1215) in cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4895.