Abstract LB-239: Genetic approaches for next generation of breast cancer tailored therapies

Abstract

Abstract Cancer therapy has radically changed during the last decade. Novel therapies based on the specific molecular changes that drive tumorigenesis in every patient are emerging as low toxicity and more efficient alternatives to classical treatments. However, even these ideal tailored therapies fail to provide a long-term cure and can only delay the progression of the disease. An alternative promising approach is the use of genetic synthetic lethal interactions. These occur when two genetic alterations that are individually innocuous appear in the same cell causing growth inhibition. This concept can be exploited to identify genes that, when inhibited, exclusively reduce the viability of tumor cells that carry a preexisting genetic lesion. Although synthetic lethality has always been proposed as an attractive anticancer approach with proven success, identification of these genetic interactions has remained elusive mainly because of the lack of proper genetic tools. However, RNA interference (RNAi) technology has emerged as a very powerful approach to attenuate the expression of any chosen gene. Thus, we envision using RNAi to identify genes that, when attenuated, exclusively reduce the viability of tumor cells carrying specific genetic lesions without affecting normal ones. During the last years, we have pioneered the development of RNAi based genetic tools for studies in mammalian cells. Thus, we have generated a highly efficient RNAi library that allows us to block any gene of interest in the human genome. Additionally, we have developed a microarray-based analytical platform that, when combined with our RNAi library, greatly facilitates genome-wide RNAi studies. This technology represents a unique opportunity to identify synthetic lethal effects with major cancer alterations. In this project we have started to apply our state-of-the-art technology to uncover synthetic lethal interaction with the major breast cancer genes (ErbB2, c-Myc, Cyclin-D1 and RB). These functional studies have already revealed that Stat-3 is synthetic lethal with activation of ErbB2. Thus, attenuating the activation levels of Stat-3 using small molecules inhibitors or RNAi silencing differentially reduced the viability of cells transformed with an ErbB2 oncogene. Mechanistically, we have linked this effect to the activation of an autocrine loop in which ErbB2 transformed cells secrete interleukin-6 (IL6) and upregulate its bona fide receptor IL6R. This activates the canonical JAK/STAT3 pathway increasing their tolerance to oncogene-induced stress. 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 LB-239. doi:10.1158/1538-7445.AM2011-LB-239