Abstract 1719: Highly adaptable triple-negative breast cancer cells as a suitable model for testing epigenetic therapies

Abstract

Abstract A major obstacle in developing effective therapies against solid tumors stems from an inability to adequately model the rare subpopulation of panresistant cancer cells that may often drive the disease. We propose a strategy for optimally modeling highly abnormal and highly adaptable human triple-negative breast cancer (TNBC) cells, and evaluating therapies for their ability to eradicate such cells. To overcome the shortcomings often associated with cell culture models, we have incorporated several features in our model including a selection of highly adaptable cancer cells based on their ability to survive a metabolic challenge. We have shown that metabolically adaptable (MA) TNBC cells efficiently metastasize to multiple organs in nude mice. Recently we have found that MA cells selected from SUM149 cell line feature an embryo-like gene expression, which may be important in generating tumor heterogeneity and therapy-resistance. Our results obtained thus far with a variety of anticancer agents support the validity of the model of realistic panresistance and suggest that it could be used for developing anticancer agents that would overcome panresistance. The cancer cells most responsible for panresistance are heterogeneous, and the likelihood that a particular test therapy will affect these cells is difficult to predict. Our testing strategy, which involves long-term evaluation of anticancer agents on MA cells in parallel with the parental cell line, is optimized to investigate the effects of potential therapeutic compounds on panresistance. This approach can not only help choose superior therapies for clinical trials, but also suggest strategies for overcoming therapeutic resistance in a timely manner. Considering an important role of chromatin in panresistance, we evaluated two promising chromatin modifiers- a bromodomain inhibitor JQ1 and a Jumonji histone demethylase inhibitor JIB-04 for their ability to overcome panresistance in our model. Both these compound appear promising in different cancer models. We are evaluating these compounds for efficacy in eradicating MA cells; we are testing these compounds to determine whether they are effective as single-agents and/or whether they can sensitize MA cells to chemotherapies. Our results indicate that a long treatment with either JQ1 or JIB-04 sensitizes MA cells to chemotherapeutic drugs doxorubicin and paclitaxel. Our results support the utility of our approach in discovering effective anticancer therapies against a heterogeneous and evolving disease like TNBC. Supported by a State of Texas Grant for Rare and Aggressive Cancers. Citation Format: Balraj Singh, Ryan D. Milligan, Hannah E. Kinne, Anna Shamsnia, Anthony Lucci. Highly adaptable triple-negative breast cancer cells as a suitable model for testing epigenetic therapies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1719. doi:10.1158/1538-7445.AM2015-1719