Epertinib counteracts multidrug resistance in cancer cells by antagonizing the drug efflux function of ABCB1 and ABCG2

Multidrug resistance (MDR) presents a major challenge in cancer treatment, often driven by the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and/or ABCG2 in cancer cells. These transporters reduce the effectiveness of chemotherapy drugs by actively pumping them out of cells, a process fueled by ATP hydrolysis that limits drug accumulation within the cells. The lack of approved therapies to address MDR complicates the treatment of resistant cancers, prompting interest in alternative strategies like drug repurposing. One promising approach involves using molecularly targeted agents to overcome MDR by inhibiting ABCB1 and/or ABCG2 activity.

Epertinib, a potent EGFR and HER2 inhibitor currently undergoing clinical trials for solid tumors, was evaluated for its potential to reverse MDR in cancer cells overexpressing ABCB1 and ABCG2. Our results show that epertinib, at sub-toxic, submicromolar concentrations, effectively restores the sensitivity of MDR cancer cells to chemotherapy in a dose-dependent manner. The data indicate that epertinib enhances drug-induced apoptosis by inhibiting the efflux functions of ABCB1 and ABCG2, without affecting their expression levels. Using ATPase assays and molecular docking, we identified potential binding sites between epertinib and the drug-binding pockets of these transporters.

In conclusion, our study highlights an additional pharmacological action of epertinib, showing its potential to modulate ABCB1 and ABCG2 activity. These findings suggest that combining epertinib with traditional chemotherapy could offer therapeutic benefits for patients with tumors overexpressing these transporters, warranting further investigation.