Abstract
Epertinib (S-222611) is a potent, reversible, and selective tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), human EGFR2 (HER2), and human EGFR4. We developed experimental brain metastasis models by intraventricular injection (intraventricular injection mouse model; IVM) of HER2-positive breast cancer (MDA-MB-361-luc-BR2/BR3) or T790M-EGFR-positive lung cancer (NCI-H1975-luc) cells. After a single oral administration, epertinib and lapatinib concentrations in brain metastatic regions were analyzed by quantitative imaging mass spectrometry. In the NCI-H1975 lung cancer IVM, the concentration of epertinib in brain metastasis was comparable to that of lapatinib. However, in the MDA-MB-361 breast cancer IVM, the concentration of epertinib in brain metastasis was >10 times higher than that of lapatinib. Furthermore, the epertinib tumor-to-normal brain ratio was ~4 times higher than that of lapatinib. Blood-tumor barrier (BTB) permeability was assessed in each brain metastatic region. In the lung cancer model, fluorescently labeled dextran was more highly detected in brain metastatic regions than in brain parenchyma. However, in breast cancer models, dextran fluorescence intensity in brain metastatic regions and brain parenchyma were comparable, suggesting that the BTB remained largely intact. Epertinib would be promised as a therapeutic agent for HER2-positive breast cancer with brain metastasis.
Highlights
Breast cancer is a heterogeneous disease with treatment options varying with biological markers
Plasma concentrations of radioactivity and epertinib were determined after a single oral administration of [14C]-epertinib hydrochloride at a dose of 5 mg/kg in rats (Supplementary Fig. S3)
The plasma concentration of radioactivity decreased from a maximum (Cmax) of 93.4 ± 16.0 ng eq./ mL at 4.00 ± 1.63 h after dosing
Summary
Breast cancer is a heterogeneous disease with treatment options varying with biological markers. Longer survival of patients with metastatic breast cancer and improved imaging techniques are associated with the increased incidence of reported brain metastasis. Lapatinib has been extensively tested in the treatment of breast cancer patients with brain metastases and clinical information, including clinical pharmacokinetic (PK)/ pharmacodynamics (PD) studies[12]. In phase I trials, epertinib has been well tolerated with efficacy against HER2-positive tumors, including breast cancer metastasized to brain[14,15,16,17]. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) was developed to directly visualize the distribution of small (drugs, lipids, and endogenous metabolites) and large molecules (peptides and proteins) in tissue sections without radiolabeling[21,22,23]. To understand the efficacy and safety of drug candidates, it is important to know both the specific distribution and concentration of a compound within the target regions
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