Abstract 1953: Elevated eukaryotic translation initiation factor 4E (eIF4E) is involved in erlotinib resistance

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, erlotinib and gefitinib, are effective therapies for non-small cell lung cancer (NSCLC) with somatic mutations in EGFR. However, all patients eventually develop resistance (i.e., acquired resistance) to these agents. Thus, there is a great challenge and urgent need to understand the underlying mechanism so as to develop effective strategies to overcome the resistance. Eukaryotic translation initiation factor 4E (eIF4E) is the rate-limiting factor for cap-dependent translation initiation, a well known mechanism that regulates oncogenesis. In human cancers, increased eIF4E expression has been documented repeatedly to be associated with malignant progression. Accordingly therapeutic suppression of eIF4E expression (e.g., with eIF4E antisense oligonucleotides) effectively reduces tumor growth. However, the role of eIF4E in regulation of erlotinib resistance has not been studied. In this study, we detected increased levels of eIF4E in 16 human NSCLC cell lines compared with their normal bronchial epithelial cells. Consistently, human tissue array analysis showed that eIF4E expression was significantly higher in human NSCLC tissues than normal tissues. Inhibition of eIF4E using eIF4E siRNA substantially inhibited the growth of NSCLC cells. These data suggest that eIF4E overexpression plays a crucial role in supporting the growth of NSCLC cells. By SILAC proteomic and subsequent Western blot analysis, we found that eIF4E levels were substantially elevated in erlotinib-resistant cell line (i.e., HCC827/ER) compared with the sensitive parental cell line (i.e., HCC827). In agreement, assembly of the eIF4F cap complex and several oncogenic proteins such as HIF1α, c-Myc, and Mcl-1, which are regulated by the cap-dependent translation mechanism, were also increased in HCC827/ER cells. Thus, it appears that erlotinib-resistant cells exhibit elevated eIF4E expression and cap-dependent translation. Inhibition of eIF4E with either siRNA or the small molecule eIF4E inhibitor, 4EGI-1, in HCC828/ER cells, partially restored cell sensitivity to erlotinib, suggesting that elevated eIF4E in part contributes to development of erlotinib resistance. In addition, we detected increased levels of eIF4E mRNA in HCC827/ER cells, suggesting that elevated levels of elF4E protein are likely due to increased transcription. Our ongoing work is devoted to understand how eIF4E levels are elevated during the development of erlotinib resistance. (This study was supported by the Georgia Cancer Coalition Distinguished Cancer Scholar award, NIH/NCI RO1 CA118450 and PO1 CA116676, and Emory Winship Cancer Institute CCB seed grant; SY Sun, FR Khuri, SS Ramaligam and RK Owonikoko are Georgia Cancer Coalition Distinguished Cancer Scholars) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1953. doi:10.1158/1538-7445.AM2011-1953