title: 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.
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.
authors: Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555 Japan.
authors: Akiko
authors: A
authors: Nakayama
authors: Shinji
authors: S
authors: Takagi
authors: Tadashi
authors: T
authors: Yusa
authors: Masahiro
authors: M
authors: Yaguchi
authors: Akira
authors: A
authors: Hayashi
authors: Toshiya
authors: T
authors: Tamura
authors: Youichi
authors: Y
authors: Kawakita
authors: Tomoyasu
authors: T
authors: Ishikawa
authors: Yoshikazu
authors: Y
authors: Ohta
keywords: TAK-285; brain metastases; dual HER2/EGFR kinase inhibitor; lapatinib; murine xenografts.
references: J Med Chem. 2011 Dec 8;54(23):8030-50
references: 22003817
references: J Med Chem. 2005 Feb 24;48(4):1107-31
references: 15715478
references: J Biopharm Stat. 1998 Jul;8(3):353-66
references: 9741852
references: Adv Drug Deliv Rev. 2003 Jan 21;55(1):83-105
references: 12535575
references: Nat Rev Cancer. 2011 May;11(5):352-63
references: 21472002
references: Brain Res Bull. 2012 Mar 10;87(4-5):413-9
references: 22245027
references: Drug Metab Dispos. 2009 Feb;37(2):439-42
references: 19056914
references: Neurosurg Focus. 2007 Mar 15;22(3):E1
references: 17608351
references: Oncologist. 2008 Jul;13(7):739-50
references: 18614587
references: Nature. 2009 Jun 18;459(7249):1005-9
references: 19421193
references: Breast Cancer Res. 2005;7(6):R1028-35
references: 16280056
references: Methods Enzymol. 2006;411:256-70
references: 16939794
references: Nat Rev Cancer. 2005 May;5(5):341-54
references: 15864276
references: Cancer Res. 2007 May 1;67(9):4190-8
references: 17483330
references: Drugs Today (Barc). 2004 Jan;40(1):5-22
references: 14988766
references: Drug Metab Dispos. 2008 Apr;36(4):695-701
references: 18216274
references: Cancer Res. 1983 Oct;43(10):4943-50
references: 6883344
references: Oncologist. 2007 Jul;12(7):766-73
references: 17673608
references: J Biol Chem. 2011 May 27;286(21):18756-65
references: 21454582