Abstract 4382: Relative expression of miR200 microRNAs and ERBB family negative regulator Mig6 in estimation of EMT status and erlotinib sensitivity

Abstract

Abstract While sensitizing mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) render tumors more sensitive to EGFR tyrosine kinase inhibitors (TKIs), these genetic alterations are present in only a minority of patients who respond to treatment and are rare in tumors other than NSCLCs. Thus, clinical benefit of TKIs in a subset of patients with wild-type EGFR may be underestimated due to the lack of appropriate predictive markers to stratify them from larger number of patients who do not response. It has long been observed that the response of anti-EGFR agents is associated with epithelial and mesenchymal transition (EMT) in multiple types of tumors without known EGFR mutations. However, little is known about the molecular mechanisms underlying this association, and no EMT-associated biomarkers of clinical utility have been successfully developed. Here we show that during the TGFβ-induced EMT, upregulation of mitogen-inducible gene 6 (Mig6), a negative regulator of EGFR, by microRNAs 200 (miR200) family is leading to reduced EGFR dependence, initiation of kinase switch in mesenchymal cells and subsequent insensitivity of these cells to EGFR inhibition. Moreover, we found that the ratio between mRNA levels of Mig6 and miR200c highly correlated with erlotinib sensitivity and EMT status in panel of 25 cancer cell lines of different tissue origins. Furthermore, analysis of directly xenografted human lung and pancreatic tumors (tumorgrafts) bearing wtEGFR demonstrated a higher response to EGFR inhibitor erlotinib for models with low Mig6 (mRNA)/miR200 ratio. Collectively, our data demonstrates that during the EMT-associated evolution of resistance to EGFR inhibitors, Mig6 expression is highly correlated with EMT status and identifies the ratio of Mig6 mRNA to miR200 as a novel, reliable and cost-effective predictor of biologic and clinical response to TKIs. Citation Format: Eugene G. Izumchenko, Xiaofei Chang, Christina Michailidi, Luciane Kagohara, Rajani Ravi, Mariana Brait, Atul Bedi, David Sidransky. Relative expression of miR200 microRNAs and ERBB family negative regulator Mig6 in estimation of EMT status and erlotinib sensitivity. [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 4382. doi:10.1158/1538-7445.AM2014-4382