Abstract 2416: Important role of FTO in the survival of rare panresistant triple-negative inflammatory breast cancer cells under a severe metabolic challenge

Abstract

Abstract Cancer is an evolution-like process. Effectively dealing with the currently untreatable component of breast cancer (the cells that drive metastasis) is vital. In this regard, we have developed a model of panresistant cancer cells that allows us to evaluate therapeutic agents to eradicate them. We have previously shown that only 0.01% cells survive a metabolic challenge involving lack of glutamine in culture medium of SUM149 triple-negative Inflammatory Breast Cancer (TN-IBC) cell line. These cells, designated as SUM149-MA for metabolic adaptability, are resistant to chemotherapeutic drugs, and they efficiently metastasize to multiple organs in nude mice. The MA cells can survive a variety of challenges in the metastasis process because of their embryo-like nature. We hypothesized that obesity-related molecular networks, which normally help in cellular and organismal survival under metabolic challenges, may help in the survival of MA cells. We found that fat mass and obesity-associated protein FTO is overexpressed in MA cells. It was reported recently that obesity-associated cis-acting elements in non-coding region of FTO regulate the expression of IRX3 gene, thus activating obesity networks. Here we found that IRX3 protein is significantly overexpressed in MA cells (4 to 5-fold) as compared to the parental SUM149 cell line, supporting our hypothesis. We utilized MO-I-500, a pharmacological inhibitor of FTO to investigate its role in MA cells. When included in a glutamine-starvation medium in 1.5 to 2 μM range, MO-I-500 significantly (>90%) inhibited survival and/or colony formation of SUM149-MA cells as compared to untreated cells or those treated with a control compound MO-I-100. Interestingly, MO-I-500 treatment had no significant effect on cell growth of either the SUM149 or SUM149-MA cell line when added to a complete medium containing glutamine that does not pose a metabolic challenge. Furthermore, SUM149-MA cells that were initially selected in a glutamine-free medium were not affected by a subsequent treatment with MO-I-500, even in glutamine-free medium. These results are significant as they reveal linkages between tumor adaptability, the embryonic nature of cancer cells, and obesity-like networks at the roots of therapy-resistant TN-IBC. They also suggest a novel approach for evaluating potential anticancer agents that would halt cancer evolution and prevent development of resistance to currently offered therapies. Supported by a State of Texas Grant for Rare and Aggressive Cancers. Citation Format: Balraj Singh, Hannah E. Kinne, Ryan D. Milligan, Laura J. Washburn, Mark Olsen, Anthony Lucci. Important role of FTO in the survival of rare panresistant triple-negative inflammatory breast cancer cells under a severe metabolic challenge. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2416.