Abstract 4085: Distribution analysis of S-222611 in brain metastases of HER2-positive breast cancer by quantitative imaging mass spectrometry: prospect for antitumor activity of EGFR/HER2/HER4 kinase inhibitor S-222611 against brain metastases
Authors: Tanaka Yukari , Hirata Michinari , Shinonome Satomi , Matsumoto Mitsunobu , Nogami Wataru , Torii Mikinori , Nezasa Ken-ichi , Tanaka Hidekazu 
Published: July 2017

Abstract
S-222611 is a potent and selective reversible tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), human EGFR2 (HER2), and human EGFR4 developed in Shionogi. Greater potency of anti-tumor activity than lapatinib was demonstrated in vitro and in animal models. In the intracranial implantation mice model implanted the HER2-positive cell line (MDA-MB-361-luc-2), S-222611 showed more potent anti-tumor activity than lapatinib. On the basis of higher penetration in brain of S-222611 than lapatinib indicated by the preclinical pharmacokinetic studies, we demonstrated the application of S-222611 to brain metastases with breast cancer. In order to enhance the clinical predictability of S-222611 to the treatment of brain metastases, we have developed the experimental brain metastases models in mice of HER2-positive breast cancer (MDA-MB-361-luc-2-BR2/BR3) or T790M-EGFR expressing lung cancer (NCI-H1975-luc). After a single oral administration of S-222611 or lapatinib, the concentrations of S-222611 and lapatinib in the brain metastatic regions of these mice models were analyzed by quantitative imaging mass spectrometry (IMS). In the NCI-H1975 lung cancer model (intraventricular injection model), the concentrations of S-222611 in brain metastases quantified by IMS were comparable to those of lapatinib. In contrast, in the MDA-MB-361 breast cancer model (intraventricular injection model), the concentrations of S-222611 in brain metastases were over 10 times higher than those of lapatinib, and the tumor-to-normal brain ratio of S-222611 was approximately 4 times higher than that of lapatinib. IMS revealed that the concentrations in brain metastases and tumor-to-normal brain ratio of S-222611 were significantly higher than those of lapatinib in the breast cancer mice model. In addition, the blood-tumor barrier (BTB) permeability in each brain metastatic region using these mice models was assessed simultaneously. In the lung cancer model, fluorescently labeled dextran was highly detected in the brain metastatic regions than brain parenchyma. However, in the breast cancer models, fluorescence intensities for dextran in the brain metastatic regions and brain parenchyma were comparable, indicating that the BTB was remained to be largely intact in brain metastases of the breast cancer model but disrupted in the lung cancer model. These results show that S-222611 is expected to be useful for the prevention and the prompt treatment of patients with HER2-positive breast cancer having brain metastases.
Citation Format: Yukari Tanaka, Michinari Hirata, Satomi Shinonome, Mitsunobu Matsumoto, Wataru Nogami, Mikinori Torii, Ken-ichi Nezasa, Hidekazu Tanaka. Distribution analysis of S-222611 in brain metastases of HER2-positive breast cancer by quantitative imaging mass spectrometry: prospect for antitumor activity of EGFR/HER2/HER4 kinase inhibitor S-222611 against brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4085. doi:10.1158/1538-7445.AM2017-4085