Human ATP-Binding Cassette Transporter ABCG2 Confers Resistance to CUDC-907, a Dual Inhibitor of Histone Deacetylase and Phosphatidylinositol 3-Kinase

Molecular Pharmaceutics
Chung-Pu WuYu-Shan Wu

Abstract

CUDC-907 is a novel, dual-acting small molecule compound designed to simultaneously inhibit the activity of histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K). Treatment with CUDC-907 led to sustained inhibition of HDAC and PI3K activity, inhibition of RAF-MEK-MAPK signaling pathway, and inhibition of cancer cell growth. CUDC-907 is currently under evaluation in phase I clinical trials in patients with lymphoma or multiple myeloma, and in patients with advanced solid tumors. However, the risk of developing acquired resistance to CUDC-907 can present a significant therapeutic challenge to clinicians in the future and should be investigated. The overexpression of ATP-binding cassette (ABC) drug transporter ABCB1, ABCC1, or ABCG2 is one of the most common mechanisms of developing multidrug resistance (MDR) in cancers and a major obstacle in chemotherapy. In this study, we reveal that ABCG2 reduces the intracellular accumulation of CUDC-907 and confers significant resistance to CUDC-907, which leads to reduced activity of CUDC-907 to inhibit HDAC and PI3K in human cancer cells. Moreover, although CUDC-907 affects the transport function of ABCG2, it was not potent enough to reverse drug resistance mediated by ABCG2 ...Continue Reading

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Citations

May 24, 2019·Journal of Cellular and Molecular Medicine·Hongyu DuanChuan Wang
Aug 19, 2017·Investigational New Drugs·Kenneth K W To, Li-Wu Fu
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Aug 29, 2019·ACS Omega·Atamjit SinghPreet Mohinder Singh Bedi

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