Lirafugratinib attenuates ABCG2-dependent drug efflux and restores chemosensitivity in multidrug-resistant nonsmall cell lung cancer cells.

The therapeutic efficacy of many anticancer drugs is frequently compromised by multidrug resistance, a process often driven by elevated activity of ATP-binding cassette (ABC) efflux pumps in tumor cells. These membrane transporters actively expel chemotherapeutic agents in an ATP-dependent fashion, thereby lowering intracellular drug exposure and diminishing treatment responses. The shortage of clinically approved agents capable of overcoming ABC transporter-mediated resistance highlights the urgency of identifying alternative approaches, including the repurposing of small-molecule targeted therapies to inhibit drug efflux. Here, we examine lirafugratinib, an orally available and highly selective fibroblast growth factor receptor 2 inhibitor currently undergoing clinical evaluation for intrahepatic cholangiocarcinoma and other solid tumors, as a potential modulator of ABCG2-mediated drug resistance. Our findings reveal that lirafugratinib, at concentrations that do not impair cell viability, restores sensitivity to ABCG2-substrate chemotherapeutic drugs and enhances apoptosis in ABCG2-overexpressing nonsmall cell lung cancer cells. Mechanistically, lirafugratinib impedes the efflux capability of ABCG2 without altering its protein expression. ATPase experiments and molecular docking analysis further indicate that lirafugratinib engages the drug-binding region of ABCG2 and modulates its ATP hydrolysis cycle. Collectively, these results suggest that lirafugratinib may be utilized as a chemosensitizing agent to counteract multidrug resistance in nonsmall cell lung cancer with high ABCG2 expression, supporting its evaluation in combination therapies. Further in vivo studies and clinical trials are required to substantiate its clinical applicability. SIGNIFICANCE STATEMENT: This work identifies lirafugratinib, a highly selective fibroblast growth factor receptor 2 inhibitor, as a previously unrecognized suppressor of ABCG2-dependent MDR. By limiting efflux-mediated depletion of anticancer drugs while maintaining its own activity, lirafugratinib resensitizes resistant nonsmall cell lung cancer cells to cytotoxic agents, supporting its potential utility in combination regimens for tumors with elevated ABCG2 expression.