J Cancer 2013; 4(7):557-565. doi:10.7150/jca.6689

Research Paper

Antitumor Activity of TAK-285, an Investigational, Non-Pgp Substrate HER2/EGFR Kinase Inhibitor, in Cultured Tumor Cells, Mouse and Rat Xenograft Tumors, and in an HER2-Positive Brain Metastasis Model

Akiko Nakayama, Shinji Takagi, Tadashi Yusa, Masahiro Yaguchi, Akira Hayashi, Toshiya Tamura, Youichi Kawakita, Tomoyasu Ishikawa, Yoshikazu Ohta

Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555 Japan.

Abstract

Breast cancer therapy has improved following the development of drugs with specific molecular targets, exemplified by inhibitors of human epidermal growth factor receptor-2 (HER2) or epidermal growth factor receptor (EGFR) such as trastuzumab and lapatinib. However, these drugs have little effect on brain metastasis due to the combined effects of poor penetration of the blood-brain barrier and their removal from the central nervous system (CNS) by the p-glycoprotein (Pgp) drug efflux pump. We investigated the effects of TAK-285, a novel, investigational, dual EGFR/HER2 inhibitor that has been shown to penetrate the CNS and has comparable inhibitory efficacy to lapatinib which is a known Pgp substrate. Tested against a panel of 96 kinases, TAK-285 showed specificity for inhibition of HER family kinases. Unlike lapatinib, TAK-285 is not a substrate for Pgp efflux. In mouse and rat xenograft tumor models, TAK-285 showed antitumor activity against cancers that expressed HER2 or EGFR. TAK-285 was as effective as lapatinib in antitumor activity in a mouse subcutaneous BT-474 breast cancer xenograft model. TAK-285 was examined in a model of breast cancer brain metastasis using direct intracranial injection of BT-474-derived luciferase-expressing cells and showed greater inhibition of brain tumor growth compared to animals treated with lapatinib. Our studies suggest that investigational drugs such as TAK-285 that have strong antitumor activity and are not Pgp substrates may be useful in the development of agents with the potential to treat brain metastases.

Keywords: TAK-285, brain metastases, dual HER2/EGFR kinase inhibitor, lapatinib, murine xenografts.

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How to cite this article:
Nakayama A, Takagi S, Yusa T, Yaguchi M, Hayashi A, Tamura T, Kawakita Y, Ishikawa T, Ohta Y. Antitumor Activity of TAK-285, an Investigational, Non-Pgp Substrate HER2/EGFR Kinase Inhibitor, in Cultured Tumor Cells, Mouse and Rat Xenograft Tumors, and in an HER2-Positive Brain Metastasis Model. J Cancer 2013; 4(7):557-565. doi:10.7150/jca.6689. Available from http://www.jcancer.org/v04p0557.htm