Abstract
Idiosyncratic lapatinib-induced liver injury has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01. In order to investigate its mechanism, interaction of lapatinib with HLA-DRB1*07:01 and its ligand peptide derived from tetanus toxoid, has been evaluated in vitro. Here we show that lapatinib enhances binding of the ligand peptide to HLA-DRB1*07:01. Furthermore in silico molecular dynamics analysis revealed that lapatinib could change the β chain helix in the HLA-DRB1*07:01 specifically to form a tightly closed binding groove structure and modify a large part of the binding groove. These results indicate that lapatinib affects the ligand binding to HLA-DRB1*07:01 and idiosyncratic lapatinib-induced liver injury might be triggered by this mechanism. This is the first report showing that the clinically available drug can enhance the binding of ligand peptide to HLA class II molecules in vitro and in silico.
Highlights
Lapatinib is an orally active dual tyrosine kinase inhibitor which interrupts the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor pathways approved for the treatment of HER2-positive advanced or metastatic breast cancer
We evaluated the effects of three drugs, lapatinib, that is clinically related to DRB1Ã07:01 specific liver injury, and amoxicillin and lumiracoxib, that are not related to it, on the binding of its ligand peptide to each human leukocyte antigen (HLA)-DR (DRB1Ã07:01 as the test allele and DRB1Ã15:01 as the control allele)
Lapatinib increased tetanus toxoid (TT) peptide binding to HLA-DRB1Ã07:01 in a dose-dependent manner, whereas amoxicillin and lumiracoxib did not exhibit increment of peptide binding for both alleles
Summary
Lapatinib is an orally active dual tyrosine kinase inhibitor which interrupts the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor pathways approved for the treatment of HER2-positive advanced or metastatic breast cancer. It is used in combination with capecitabine for patients who have received previous therapy including an anthracycline, a taxane and trastuzumab, and in combination with letrozole for the treatment of postmenopausal women with hormone receptor–positive breast cancer [1,2]. The expressions of these two alleles are highly correlated, comparisons of HLA-DR and HLA-DQ heterodimer protein pairing suggested the PLOS ONE | DOI:10.1371/journal.pone.0130928 June 22, 2015
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