Abstract 509: Novel role of MeCP2 in response to EGFR targeted therapy

Abstract

Abstract One of the targets towards the development of new agents to combat cancer is the inhibition of epidermal growth factor receptor (EGFR). A therapeutic antibody to EGFR, cetuximab, is seen to be effective in combination with cisplatin or radiation. However, only one out of four patients treated benefit from this therapy. It is therefore important to identify patients who can gain from this treatment. We hypothesize that through phosphoproteome analysis, we can identify alterations in novel signal transduction molecule(s) induced by cetuximab treatment in sensitive cell lines or TMA that will predict response to treatment. Phosphoproteomic changes upon cetuximab treatment in UMSCC-1 (cetuximab-responsive) and UMSCC-74B (cetuximab-non-responsive) cell lines using nonporous silica reverse-phase high performance liquid chromatography (NPS-RP-HPLC) were assessed. To confirm the results of phosphoproteomics data, three proteins that were seen to be affected in the sensitive cell line were investigated by immunoprecipitating total proteins followed by immunoblotting with phospho-specific antibodies. We found pharmacodynamic changes in 12 novel proteins upon cetuximab treatment in UMSCC-1 cell line. By Immunoblotting, we confirmed that these three proteins (methyl-CpG binding proteins) are indeed phosphorylated at serine, threonine and tyrosine sites. Cetuximab treatment in UMSCC-1, induced phosphorylation of NCoR1 and MeCP2 (which cause transcriptional repression) and decreased phosphorylation of MBD2 (which causes transcriptional activation), thus confirming the phosphoproteomic data. In contrast, the phosphoproteomics data in UMSCC-74B indicated either no effect or an opposing effect to that seen in the sensitive cells. These data suggest that we have a powerful strategy to identify novel phosphoproteins that are affected by EGFR inhibition and thus, novel biomarkers of response to cetuximab. These and additional biomarkers that we hope to discover will undergo rigorous in vitro and in vivo testing before employing them on TMA from xenografts. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 509.