BLU-945 suppresses ABCB1-mediated drug efflux and restores chemosensitivity in multidrug-resistant cancer cells.

Authors

Chung-Pu Wu, Yen-Ching Li, Ting-Yu Chen, Hui-Chiau Chuang, Bing-Huan Lin, Megumi Murakami, Yu-Tzu Chang, Yu-Shan Wu, Tai-Ho Hung, Suresh V Ambudkar

Published in

European journal of pharmacology. Pages 179220. Aug 11, 2026. Epub Aug 11, 2026.

Abstract

Chemotherapy remains a cornerstone of cancer treatment, yet its clinical efficacy is often limited by multidrug resistance (MDR). A major contributor to this phenomenon is the ATP-binding cassette transporter ABCB1 (P-glycoprotein; P-gp), which actively exports many chemotherapeutic agents from cancer cells, reducing intracellular drug accumulation and therapeutic effectiveness. Despite decades of effort, clinically effective ABCB1 inhibitors capable of overcoming this resistance mechanism have not been successfully developed. In this study, we examined whether BLU-945, a fourth-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor designed to target resistant EGFR mutations, could also modulate ABCB1 activity. Our findings demonstrate that BLU-945 stimulates ABCB1 ATPase activity, indicating direct interaction with the transporter consistent with substrate or modulator behavior. Notably, ABCB1-overexpressing cancer cells did not exhibit resistance to BLU-945, suggesting that elevated ABCB1 expression does not compromise its intrinsic anticancer activity. More importantly, BLU-945 significantly restored the sensitivity of ABCB1-overexpressing cancer cells to multiple cytotoxic agents in a concentration-dependent manner at sub-cytotoxic concentrations. Mechanistic studies further revealed that this chemosensitizing effect results from inhibition of ABCB1-mediated drug efflux rather than alterations in ABCB1 protein expression, leading to increased intracellular drug accumulation and enhanced cytotoxicity. Together, these findings reveal a previously unrecognized property of BLU-945 as a functional inhibitor of ABCB1-mediated drug transport. In addition to its activity as a mutant-selective EGFR inhibitor, BLU-945 may therefore serve as a dual-function agent capable of targeting oncogenic signaling while mitigating transporter-mediated chemoresistance, supporting its potential reprofiling in combination chemotherapy for ABCB1-overexpressing tumors.

PMID:
42580505
Bibliographic data and abstract were imported from PubMed on 12 Aug 2026.

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