NIH Research Festival
A major difficulty in treating cancer is the development of cellular resistance to chemotherapeutics, a phenomenon known as multidrug resistance (MDR). MDR is primarily conferred by an upregulation of ATP-binding cassette (ABC) transporters, most notably P-glycoprotein (P-gp, MDR1, ABCB1), which are responsible for the active transport of drugs out of the cells thereby minimizing drug-target interactions. While numerous strategies to overcome transporter-mediated MDR have been explored, none have proved successful. An alternative approach is to exploit resistance by identifying drugs that target MDR cells over the nonresistant parental cells from which they were selected. As such, the development of MDR1-selective agents represents a novel and relatively unexplored strategy for resolving multidrug resistance. To identify such agents, we developed a series of robust, high-throughput assays to examine differential toxicity between drug-naïve cancer cell lines and their drug-selected, multidrug-resistant sublines. We performed high-throughput screens against several libraries of annotated compounds including the NCATS Pharmaceutical Collection (NPC), a comprehensive collection of all clinically approved drugs – to identify P-gp substrates, and classes of small molecules that exhibit selective toxicity against MDR tumor lines. Further mechanistic evaluation of these compounds has provided valuable insight into targets or pathways that appear to have been rendered more sensitive to inhibition in the course of multidrug resistance development.
Scientific Focus Area: Cancer Biology
This page was last updated on Friday, March 26, 2021