Abstract 4073: Antitumor activities of EGFR/HER2/HER4 kinase inhibitor S-222611 in the experimental brain metastases of HER2-positive breast cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 13_Supplement; p. 4073
• Main Authors: Hirata, Michinari, Tanaka, Yukari, Shinonome, Satomi, Yamada, Tomomi, Torii, Mikinori, Nezasa, Ken-ichi, Tanaka, Hidekazu
• Format: Journal Article
• Language: English
• Published: 01.07.2017
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-4073

Abstract S-222611 is an oral, reversible tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), human EGFR2 (HER2) and human EGFR4 (HER4) with antitumor activities in animal models expressing these proteins. In phase I trials, S-222611 have shown to be well-tolerated with efficacy against HER2-positive tumors, including breast cancer metastatic to brain. The purpose of this study is to evaluate the mode of action for S-222611 treatment in brain metastasis using experimental mice models. At first, we examined the effect of S-222611 on HER2-positive breast cancer cell “MDA-MB-361” intracranial implantation model (ICM). Once daily oral administration of S-222611 significantly reduced the tumor volume at doses ranging from 25 to 100 mg/kg and the ED50 value was 21.2 mg/kg. Furthermore, S-222611 showed the survival prolonging activity in the ICM and the activity was significantly superior to that of lapatinib. It is known that patients with breast cancers having brain metastases display heterogeneous blood-tumor barrier (BTB) permeability that affects drug delivery and efficacy, also BTB integrities were reported to be disrupted in the ICM. To understand the mode of action for S-222611 in patient whose BTB was intact, we have developed the experimental brain metastases model by serial in vivo passage (MDA-MB-361 intraventricular injection model; IVM). BTB integrities in IVM were confirmed to be largely remaining intact by fluorescently labeled dextran incorporation study, and we examined the distribution of S-222611 on this model after single oral administration at the clinical relevant dose (50 mg/kg). By imaging mass spectrometry analysis, S-222611 concentration in the brain metastases of the IVM was significantly higher than that of lapatinib. The concentrations of S-222611 in the brain metastases of the IVM showed 5.2 µmol/L, which was remarkably higher than the in vitro IC50 value (26.5 nmol/L) of S-222611 for growth inhibition of MDA-MB-361, indicating that S-222611 could have potent antitumor activity in the brain metastases even though the intact BTB was remained. In fact, once daily oral administration of S-222611 significantly reduced the tumor volume in the brain at 50 mg/kg on the IVM. Taken together, in vitro/in vivo antitumor studies for MDA-MB-361 supported that S-222611 could be effective against brain metastases which have both intact and permeable BTB. In conclusion, S-222611 is expected to be useful for the treatment of patients with HER2-positive breast cancers, including those with brain metastases. Citation Format: Michinari Hirata, Yukari Tanaka, Satomi Shinonome, Tomomi Yamada, Mikinori Torii, Ken-ichi Nezasa, Hidekazu Tanaka. Antitumor activities of EGFR/HER2/HER4 kinase inhibitor S-222611 in the experimental brain metastases of HER2-positive breast cancer [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 4073. doi:10.1158/1538-7445.AM2017-4073