Befotertinib restored chemosensitivity to multidrug-resistant cancer cells by inhibiting the drug efflux activity of ABCB1

  • J Pharm Pharmacol. 2026 Mar 5;78(3):rgag020. doi: 10.1093/jpp/rgag020.
Yen-Ching Li  1 ,  Megumi Murakami  2 ,  Yang-Hui Huang  1 ,  Yu-Shan Wu  3 ,  Tai-Ho Hung  4  5  6 ,  Suresh V Ambudkar  2 ,  Chung-Pu Wu  1  4  7  8
Affiliations
  • 1. Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan 33302, Taiwan.
  • 2. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, United States.
  • 3. Department of Chemistry, Tunghai University, No. 1727, Sec. 4, Taiwan Boulevard, Xitun Dist., Taichung 40704, Taiwan.
  • 4. Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, No. 199, Dunhua N. Rd., Songshan Dist., Taipei City 105406, Taiwan.
  • 5. Department of Medicine, College of Medicine, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan 33302, Taiwan.
  • 6. Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, No. 222, Maijin Rd., Anle Dist., Keelung 20401, Taiwan.
  • 7. Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan 33302, Taiwan.
  • 8. Molecular Medicine Research Center, College of Medicine, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan 33302, Taiwan.
PMID: 41838808 DOI: 10.1093/jpp/rgag020
Abstract

Objectives: Chemotherapy remains central to Cancer management, but its effectiveness is often limited by multidrug resistance (MDR), largely mediated by the ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein; P-gp). As no clinically approved inhibitors are available to overcome ABCB1-mediated MDR, this study aimed to evaluate befotertinib (D-0316), a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved by the National Medical Products Administration, for its potential to modulate ABCB1 activity.

Methods: Cytotoxicity and Apoptosis assays were used to assess chemosensitization in multidrug-resistant Cancer cells. Drug efflux inhibition was examined, while vanadate-sensitive ATPase activity and molecular docking analyses were performed to characterize interactions between befotertinib and ABCB1.

Key findings: Befotertinib significantly enhanced Anticancer drug-induced Apoptosis and resensitized resistant cells in a concentration-dependent manner. It inhibited ABCB1-mediated efflux, stimulating ATPase activity and demonstrating direct binding to key residues within the ABCB1 substrate-binding pocket.

Conclusions: These results identify befotertinib as a functional inhibitor of ABCB1 with the capacity to reverse MDR. The findings support its potential as a repurposed agent for combination therapy in tumors with high ABCB1 expression, offering a practical strategy to enhance chemotherapy efficacy.

Keywords
ABC transporter; D-0316; P-glycoprotein; drug repurposing; multidrug resistance.
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