Preclinical evaluation of afatinib (BIBW2992) in esophageal squamous cell carcinoma (ESCC)
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AbstractEsophageal squamous cell carcinoma (ESCC) is the eighth most common cancer worldwide. Epidermal growth factor receptors (EGFR) are often overexpressed in esophageal cancers, thus anti-EGFR inhibitors have been evaluated in ESCC. Afatinib was an irreversible inhibitor of these ErbB family receptors. This study characterized the preclinical activity of afatinib in five ESCC cell lines: HKESC-1, HKESC-2, KYSE510, SLMT-1 and EC-1. ESCC cell lines were sensitive to afatinib with IC50 concentrations at lower micro-molar range (at 72 hour incubation: HKESC-1 = 0.002 mu M, HKESC-2 = 0.002 mu M, KYSE510 = 1.090 mu M, SLMT-1 = 1.161 mu M and EC-1 = 0.109 mu M) with a maximum growth inhibition over 95%. Afatinib can strongly induce G(0)/G(1) cell cycle arrest in HKESC-2 and EC-1 in a dose-and time-dependent manner. The phosphorylation of ErbB family downstream effectors such as pAKT, pS6 and pMAPK were significantly inhibited in HKESC-2 and EC-1. Apoptosis was observed in both cell lines at 24 hours after exposure to afatinib, as determined by the presence of cleaved PARP. Afatinib could effectively inhibit HKESC-2 tumor growth in mice without obvious toxicity. Afatinib alone has shown excellent growth inhibitory effect on ESCC in both in vitro and in vivo models, however, no synergistic effect was observed when it was combined with chemotherapeutic agents such as 5-fluorouracil (5-FU) and cisplatin. In summary, afatinib can inhibit cell proliferation effectively by arresting the cells in G(0)/G(1) phase, as well as inducing apoptosis in ESCC. These findings warrant further studies of afatinib as therapeutic agent in treating ESCC.
All Author(s) ListWong CH, Ma BBY, Hui CWC, Tao Q, Chan ATC
Journal nameAmerican Journal of Cancer Research
Volume Number5
Issue Number12
Pages3588 - 3599
LanguagesEnglish-United Kingdom
KeywordsAfatinib; AKT; EGFR; ESCC; HER2
Web of Science Subject CategoriesOncology

Last updated on 2022-19-01 at 00:46