Abstract 1834: Targeting ABC transporters in cancer through small molecule inhibitors

Abstract

Abstract Multidrug resistance is one of the major causes of treatment failure in cancer therapy. While multidrug transporter proteins are known for their contributions to chemoresistance and efflux of anti-cancer drugs from cancer cells, a significant body of evidence points to their fundamental roles in tumour biology (Fletcher et al, Nature Rev Cancer, 10:147-156, 2010). We have investigated the ABCC subfamily of multidrug transporter genes in the highly malignant and aggressive childhood solid tumour, neuroblastoma and found that high levels of ABCC1 and ABCC4 are powerful independent prognostic indicators of clinical outcome. However, the agents used to treat the patients described in these studies are not known substrates of ABCC4 and we have shown that siRNA-mediated knockdown of ABCC4 results in reduced proliferation and enhanced morphological differentiation of neuroblastoma cells, in the absence of any cytotoxic drug treatment (Henderson et al, JNCI, 103;1-16, 2011). The aim of this study is to develop a potential new approach for the treatment of neuroblastoma through the inhibition of ABCC4 using small molecule inhibitors. A cell-based screen of a library of diverse chemical small molecules was used to isolate potent small molecule inhibitors of ABCC4 that were able to sensitize HEK293 cells over-expressing MRP4 to a cytotoxic MRP4 substrate, 6-mercaptopurine (6MP). Filtering of compounds based upon their ability to cause 6MP accumulation, together with focused library screening, have resulted in the identification of several chemical structures able to specifically block MRP4. In addition to reversing drug resistance to 6MP, these compounds cause morphological differentiation and inhibition of cell growth, as seen with MRP4 siRNA, in the BE2C neuroblastoma cell line. Importantly, these compounds significantly potentiate morphological differentiation caused by the established differentiation agent, all-trans retinoic acid. We further show that these inhibitors have potency in other MRP4 expressing cancer cell lines beyond neuroblastoma. These pharmacological inhibitors offer clinical potential for the treatment of neuroblastoma and other MRP4 overexpressing cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1834. doi:1538-7445.AM2012-1834