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|Ref Type||Journal Article|
|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|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|