Abstract IA6: Genetic strategies for next generation of breast cancer therapies

Abstract

Abstract One of the major challenges for modern cancer treatments is the ability to eliminate tumor cells without affecting normal cell homeostasis. We propose to identify the “Achilles' heel” of cancer cells using the novel concept of the “noncancer addition.” Additionally to alterations in bona-fide cancer genes, in a tumor cell, multiple normal regulatory networks have been rearranged in order to adapt to the tumorigenic state. As consequence of this divergence, survival of cancer cells also depends on noncancer genes that are essential to maintain the tumor homeostasis. Therefore, we postulate that interfering with these noncancer dependencies will result in system failure, that is, the cessation of the tumorigenic state. We are combining the power of interactome-prediction models with the state-of-the-art RNAi-genetic approaches to block the function of every gene in the entire genome to find genetic synthetic lethal interactions between noncancer genes and bona-fide cancer genes. Recently, we have applied this strategy searching for novel therapeutic alternatives for ErbB2 positive breast cancer patients. ErbB2 is a receptor tyrosine kinase found overexpressed in 20-40% of breast tumors (ErbB2+ tumors) and correlates with poor prognosis. Different targeted therapies have been developed to specifically inhibit its activity. Unfortunately, the majority of these patient tumors eventually progress acquiring resistance. Thus, there is the need to find alternative tumor targets to develop specific, more efficient, treatments for these patients. By combining genome-wide RNAi loss-of-function screens with system biology interactome models we have recently found that the JAK/STAT3 pathway is activated in ErbB2 overexpressing breast cancers through an autocrine loop mediated by the secretion of Interleukin-6 (IL-6). Importantly, blockage of this pathway strongly reduced the viability of ErbB2+ cancer cells. The identification of Stat3 as a tumor target in ErbB2+ tumors opens new avenues for patients which tumors have become refractory to standard protocols. Citation Format: Jose M. Silva. Genetic strategies for next generation of breast cancer therapies [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr IA6.