title: HER2 and HER3 cooperatively regulate cancer cell growth and determine sensitivity to the novel investigational EGFR/HER2 kinase inhibitor TAK-285.
abstract: The human epidermal growth factor receptor (HER) family plays a major role in cancer cell proliferation. Overexpression of these receptors occurs in various cancers, including breast cancer, and correlates with shorter time to relapse and lower overall survival. We recently reported that TAK-285, an orally bioavailable small molecule inhibitor of HER kinases, is not a p-glycoprotein substrate and penetrates the blood-brain barrier, suggesting favorable activity for the treatment of brain metastases. To identify the determinants of sensitivity to TAK-285, we examined the relationship between the IC50 values of TAK-285 for cell growth inhibition and the expression of candidate genes that are involved in the HER family signaling pathway and trastuzumab resistance in a panel of human breast cancer cell lines, other types of cancer cells, and non-transformed cells in vitro. These analyses showed an inverse correlation between sensitivity to TAK-285 (IC50 values) and HER2 or HER3 expression. HER3 was highly phosphorylated in TAK-285-sensitive cells, where TAK-285 treatment reduced HER3 phosphorylation level. Because HER3 does not possess kinase activity and a selective inhibitor of HER2 but not of an epidermal growth factor receptor reduced the phospho-HER3 level, HER3 was suggested to be trans-phosphorylated by HER2. HER3 knockdown using small interfering RNA (siRNA) inhibited cancer cell growth in TAK-285-sensitive cells but not in TAK-285-insensitive cells. These results suggest that HER2 and HER3 mainly regulate cancer cell growth in TAK-285-sensitive cells and that phospho-HER3 could be used as a potential molecular marker to select patients most likely to respond to TAK-285.
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Fujisawa, Kanagawa, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takagi
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Fujisawa, Kanagawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Banno
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Fujisawa, Kanagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Fujisawa, Kanagawa, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Fujisawa, Kanagawa, Japan.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Fujisawa, Kanagawa, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ohta
keywords: EGFR; HER2; HER3; TAK-285; drug sensitivity; kinase inhibitor