Abstract 1333: Combining Afatinib and Cetuximab synergistically increases their cytotoxicity for EGFR T790M-harboring cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-10, Vol.74 (19_Supplement), p.1333-1333
• Main Authors: Tanaka, Nobuyuki, Watanuki, Zenta, Fukuhara, Tatsuro, Maemondo, Makoto
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2014-1333

Epidermal growth factor receptor (EGFR) is an important therapeutic target for non-small cell lung cancers (NSCLCs). Tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, are effective for patients with EGFR-activating mutations. However, these patients eventually develop resistance, usually through a secondary EGFR mutation, T790M: substitution of methionine for threonine at position 790 in the kinase domain. While second-generation irreversible TKIs have higher affinities for the double-mutant EGFRs, their therapeutic effect leaves room for improvement. Combining a second-generation TKI like afatinib with an anti-EGFR monoclonal antibody has been shown to improve clinical outcomes, although the mechanism is not fully understood. To investigate this mechanism, we used human erythroleukemia K562 cells, which are EGFR-negative, to establish cells with known EGFR mutations. Two activating EGFR mutations, Ex19del and L858R, were sensitive to first-generation TKIs. Acquisition of resistance to these TKIs was confirmed by adding the second EGFR mutation, T790M. Double-mutant EGFRs were moderately sensitive to afatinib, but were only minimally affected by the monoclonal anti-EGFR antibody cetuximab. Combining afatinib and cetuximab synergistically increased cytotoxity for K562 cells carrying double-mutant EGFRs. Apoptosis in these cells was preceded by induction of the pro-apoptotic protein BIM (Bcl2L11) and activation of Caspase-3 and PARP. Afatinib induced autophagy in these cells correlated with AKT and ERK1/2 signaling in the course of treatment. Accordingly, we found that cetuximab enhanced the afatinib-induced cytotoxicity through the autophagic cell death pathway. Our results indicate that two distinct mechanisms contribute to the synergistic effect exerted by afatinib and cetuximab against NSCLCs. Citation Format: Nobuyuki Tanaka, Zenta Watanuki, Tatsuro Fukuhara, Makoto Maemondo. Combining Afatinib and Cetuximab synergistically increases their cytotoxicity for EGFR T790M-harboring cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1333. doi:10.1158/1538-7445.AM2014-1333