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Am J Cancer Res. 2015 Nov 15;5(12):3588-99. eCollection 2015.

Preclinical evaluation of afatinib (BIBW2992) in esophageal squamous cell carcinoma (ESCC).

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State Key Laboratory of Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong Shatin, New Territories, Hong Kong SAR, China.


Esophageal 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 μM, HKESC-2 = 0.002 μM, KYSE510 = 1.090 μM, SLMT-1 = 1.161 μM and EC-1 = 0.109 μM) with a maximum growth inhibition over 95%. Afatinib can strongly induce G0/G1 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 G0/G1 phase, as well as inducing apoptosis in ESCC. These findings warrant further studies of afatinib as therapeutic agent in treating ESCC.


AKT; Afatinib; EGFR; ESCC; HER2


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