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Ref Type Journal Article
PMID (25594012)
Authors Takagi S, Banno H, Hayashi A, Tamura T, Ishikawa T, Ohta Y
Title HER2 and HER3 cooperatively regulate cancer cell growth and determine sensitivity to the novel investigational EGFR/HER2 kinase inhibitor TAK-285.
Journal Oncoscience
Vol 1
Issue 3
Date 2014
Abstract Text 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 over exp stomach cancer sensitive TAK-285 Preclinical Actionable In a preclinical study, the N87 gastric cancer cell line, which has been demonstrated to have ERBB2 (HER2) amplification and over expression, was sensitive to TAK-285, inhibiting phosphorylation of ERBB2 (HER2) and ERBB3 (HER3) (PMID: 25594012, PMID: 18441328). 18441328 25594012