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Ref Type Journal Article
PMID (26437915)
Authors Tian C, Ding P, Yuan Z, Li H, Zhao Y, Sun L, Guo Q, Wang Z, Zhang L, Jiang Z
Title A novel dual EGFR/HER2 inhibitor KU004 induces cell cycle arrest and apoptosis in HER2-overexpressing cancer cells.
Journal Apoptosis : an international journal on programmed cell death
Vol 20
Issue 12
Date 2015 Dec
URL
Abstract Text Human epidermal growth factor receptor 2 (HER2) is a validated therapeutic target in cancer therapy, and HER2 protein-tyrosine kinase inhibitors have attracted considerable attention in the field of searching for novel anticancer drug candidates. In this study, we investigated the anticancer effect of KU004, a novel dual EGFR and HER2 inhibitor in vitro and in vivo. In vitro, KU004 preferentially inhibited the growth of HER2-overexpressing breast and gastric cell lines and HER2 expression level significantly correlated with response to KU004. It blocked activation of EGFR, HER2 and downstream Akt and Erk and induced G0/G1 arrest which was associated with downregulation of p53, p21, cyclin D1 and CDK4 along with increase of p27 and dephosphorylation of pRb. Apoptosis occurred in a caspase-dependent manner mainly via the extrinsic apoptotic pathway after KU004 treatment. The in vitro efficacy of KU004 was comparable to that of lapatinib. Moreover, KU004 suppressed the growth of NCI-N87 tumor and induced apoptosis without causing apparent weight loss or obvious toxicity. Tumor volume was significantly smaller in KU004-treated group than that in lapatinib-treated group at comparable dose levels. Taken together, these findings demonstrate KU004 can be expected to be a promising anti-HER2 candidate.

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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
KU004 KU004 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
KU004 EGFR Inhibitor (Pan) 47 HER2 Inhibitor 25 KU004 is a quinazoline derivative with structural similarity to lapatinib inhibiting both Egfr and Erbb2 (Her2) in vitro (PMID: 26437915, PMID: 28532652).
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 breast cancer sensitive KU004 Preclinical Actionable In a preclinical study, KU004 inhibited growth and induced apoptosis in breast cancer cell lines over expressing ERBB2 in culture (PMID: 26437915). 26437915
ERBB2 over exp stomach cancer sensitive KU004 Preclinical Actionable In a preclinical study, KU004 inhibited growth and induced apoptosis in gastric cancer cell lines over expressing ERBB2 in culture and suppressed growth in a dose dependent manner in xenograft models (PMID: 26437915). 26437915