Abstract 3697: SIRT2 is a modulator of response to targeted therapies through regulation of MEK kinase activity

Abstract

Abstract Resistance to targeted therapies is a major problem in cancer treatment. The Epidermal Growth Factor Receptor (EGFR) antibody drugs are effective in a subset of colorectal cancers, but the molecular mechanisms of resistance are understood poorly. Genes involved in epigenetic regulation are frequently deregulated in cancer, raising the possibility that such genes also contribute to drug resistance. To address this question, we compiled an shRNA library for chromatin modifying enzymes, chromatin remodelers, and many other factors associated with chromatin regulation. Using this library, we performed a loss of function genetic screen in colon cancer cell lines sensitive to EGFR inhibitors. We identified SIRT2, a NAD+ dependent deacetylase, as a modulator of the response to EGFR inhibitors in colon and lung cancer. Mechanistically, loss of SIRT2 expression enhanced MEK acetylation, resulting in increased ERK activity. Conversely, overexpression of SIRT2 led to reduced phospho ERK and inhibition of growth. SIRT2 loss also conferred resistance to BRAF and MEK inhibitors in BRAF mutant melanoma and KRAS mutant colon cancers, respectively. These results warrant a further investigation into a potential role of SIRT2 in resistance to drugs that act in the Receptor Tyrosine Kinase-RAS-RAF-MEK-ERK signaling pathway. Citation Format: Prashanth K. Bajpe, Anirudh Prahallad, Hugo Horlings, Iris Nagtegaal, Roderick Beijersbergen, Rene Bernards. SIRT2 is a modulator of response to targeted therapies through regulation of MEK kinase activity. [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 3697. doi:10.1158/1538-7445.AM2014-3697