2. Academic Validation
  3. Structural basis for the reversal of human MRP4-mediated multidrug resistance by lapatinib

Structural basis for the reversal of human MRP4-mediated multidrug resistance by lapatinib

  • Cell Rep. 2025 Apr 22;44(4):115466. doi: 10.1016/j.celrep.2025.115466.
Zhipeng Xie 1,  Jiaxiang Lv 1,  Wei Huang 1,  Zhikun Wu 1,  Rongli Zhu 1,  Zixin Deng 2,  Feng Long 3
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
  • 2 Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
  • 3 Department of Neurosurgery, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: longfe@whu.edu.cn.
PMID: 40138312 DOI: 10.1016/j.celrep.2025.115466
Abstract

Multidrug resistance proteins (MRPs) are one of the major mechanisms for developing Cancer Drug Resistance. Human MRP4 (hMRP4) plays an important role in various chemotherapy-resistant cancers. Here, we show hMRP4 mediates the resistance of a broad spectrum of antitumor reagents in the cultured tumor cells, among which the cell resistance to vincristine and 5-fluorouracil is rescued by supplementing a Tyrosinase Inhibitor, lapatinib. The cryoelectron microscopy (cryo-EM) structures of hMRP4 in the substrate- or inhibitor-bound form are determined. Although lapatinib shares partial binding sites with vincristine and 5-fluorouracil using a similar set of crucial residues located in the central cavity of hMRP4, the high binding affinity of lapatinib and its unique binding mode with transmembrane helices TM2 and TM12 inside the pathway tunnel prohibit hMRP4 from structural transition between intermediate states during drug translocation. This study provides mechanistic insights into the therapeutical potential of lapatinib in combating hMRP4-mediated MDR.

Keywords

ABCC4; CP: Molecular biology; MRP4; MRP4 inhibitors; cryo-EM structures; inhibition mechanism; lapatinib; multidrug resistance proteins; reversal of drug resistance.

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