In:
Cancer Science, Wiley, Vol. 105, No. 8 ( 2014-08), p. 1040-1048
Abstract:
Epidermal growth factor receptor ( EGFR ) and human epidermal growth factor receptor 2 ( HER 2) are validated molecular targets in cancer therapy. Dual blockade has been explored and one such agent, lapatinib, is in clinical practice but with modest activity. Through chemical screening, we discovered a novel EGFR and HER 2 inhibitor, S ‐222611, that selectively inhibited both kinases with IC 50 s below 10 nmol/L. S‐222611 also inhibited intracellular kinase activity and the growth of EGFR ‐expressing and HER 2‐expressing cancer cells. In addition, S ‐222611 showed potent antitumor activity over lapatinib in a variety of xenograft models. In evaluations with two patient‐oriented models, the intrafemoral implantation model and the intracranial implantation model, S ‐222611 exhibited excellent activity and could be effective against bone and brain metastasis. Compared to neratinib and afatinib, irreversible EGFR / HER 2 inhibitors, S ‐222611 showed equivalent or slightly weaker antitumor activity but a safer profile. These results indicated that S ‐222611 is a potent EGFR and HER 2 inhibitor with substantially better antitumor activity than lapatinib at clinically relevant doses. Considering the safer profile than for irreversible inhibitors, S ‐222611 could be an important option in future cancer therapy.
Type of Medium:
Online Resource
ISSN:
1347-9032
,
1349-7006
DOI:
10.1111/cas.2014.105.issue-8
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
2115647-5
detail.hit.zdb_id:
2111204-6
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