The fourth-generation EGFR tyrosine kinase inhibitor BLU-945 resensitizes ABCG2-overexpressing multidrug-resistant non-small cell lung cancer cells to cytotoxic anticancer drugs.

ABCG2, a key ATP-binding cassette (ABC) transporter, contributes significantly to multidrug resistance (MDR) by actively effluxing a wide range of chemotherapeutic agents from cancer cells, thereby lowering intracellular drug concentrations and reducing therapeutic efficacy. This mechanism poses a major challenge in treating cancers such as non-small-cell lung cancer (NSCLC). Despite extensive research, no clinically approved agents specifically target ABCG2-mediated MDR. Given the success of combining tyrosine kinase inhibitors (TKIs) with chemotherapy, we explored whether BLU-945, a fourth-generation epidermal growth factor receptor (EGFR) TKI with potent activity against resistant EGFR mutations, could modulate ABCG2 function to reverse MDR. Our findings reveal that BLU-945 stimulates the ATPase activity of ABCG2, indicating direct interaction as a potential substrate or modulator. However, ABCG2-overexpressing NSCLC cells did not display resistance to BLU-945, suggesting that its antitumor activity remains intact despite high ABCG2 expression. Importantly, BLU-945 significantly resensitized these resistant cells to multiple cytotoxic agents in a concentration-dependent manner, with effects evident even at nanomolar levels. Mechanistic studies indicate that this chemosensitizing effect results from functional inhibition of ABCG2-mediated drug efflux, without affecting ABCG2 protein expression, thereby enhancing intracellular drug retention and cytotoxicity. These findings reveal a previously unrecognized pharmacological property of BLU-945 as an inhibitor of ABCG2-mediated drug efflux, supporting its potential role in combination therapies aimed at overcoming MDR in patients with ABCG2-overexpressing tumors. Further preclinical and clinical studies are warranted to validate the translational relevance of this approach and to identify patient populations that may benefit most from this combinatorial strategy.