Wu ZX, et al. Cancer Sci 2020.
One pivotal factor that leads to multidrug resistance (MDR) is the overexpression of ABCG2. Therefore, tremendous effort has been devoted to the search of effective reversal agents to overcome ABCG2-mediated MDR. CC-671 is a potent and selective inhibitor of both TTK (Human Protein Kinase Monopolar Spindle 1 (hMps1)) and CDC Like Kinase 2 (CLK2). It represents a new class of cancer therapeutic drugs. In this study, we demonstrate that CC-671 is an effective ABCG2 reversal agent that enhances the
efficacy of chemotherapeutic drugs in ABCG2-overexpressing lung cancer cells. Mechanistic studies show that the reversal effect of CC-671 is primarily attributed to the inhibition of the drug efflux activity of ABCG2, which leads to increased intracellular level of chemotherapeutic drugs. Besides, CC-671 does not alter the protein expression of ABCG2 and subcellular localization of ABCG2. The computational molecule docking analysis suggests CC-671 has high binding affinity to the drug-binding site of ABCG2. In conclusion, we reveal the interaction between CC-671 and ABCG2, providing a rational of potential combinational use of CC-671 with ABCG2 substrate to overcome MDR.