Abstract 2003: Evaluation of 6-mercaptopurine in a cell culture model of adaptable triple-negative breast cancer with metastatic potential

Abstract

Abstract Even after an early diagnosis, surgery, radiation, and adjuvant chemotherapy, some triple-negative breast cancers (TNBC) relapse within a year. Some patients, e.g., those with persistent minimal residual disease (MRD) at the end of currently offered therapies after surgery, have a high likelihood of disease relapse. The biggest challenge is to identify the therapies that are safe and effective in halting the progression of poor-prognosis MRD (which efficiently switches between quiescence and proliferation) to metastasis/recurrence. Progenitor-like cancer cells that can survive in reversible quiescence when faced with various challenges in the body, including immune attacks and currently offered therapies, are often behind disease progression to metastasis. A lack of glutamine in culture medium, which eliminates >99.9% of proliferating SUM149 TNBC cells, selects such adaptable, panresistant cells, similar to a selection of highly resistant cancer cells in poorly perfused regions of cancer. Our data support the hypothesis that a lack of glutamine forces the selection of an epigenetic state that does not require a high level of TET2, thus selecting an “undifferentiated” therapy-resistant phenotype as seen in TET2-mutant cancers. Investigations of these adaptable cells (functional studies and molecular analyses) have revealed a variety of ways (genetic mutations, modifications of epigenome, transcriptome, proteome, etc.) that could generate a tremendous cellular heterogeneity and confer survival advantage under various bottlenecks in the body. Our data suggesting that highly adaptable cells are generated through reprograming of the epigenome and transcriptome (indicated by gene expression changes in ZEB1, TET2, ESRP1, ESRP2, FTO, ADARB1, ADARB2, etc.) led us to evaluate low-dose 6-mercaptopurine (6-MP) as a potential therapy in our model of adaptable cancer cells. We chose 6-MP based on its ability to induce and maintain remission in inflammatory bowel disease and childhood acute lymphoblastic leukemia, thus having a potential to be repurposed for treating the TNBC that is at high risk of relapse. We found that long treatment with low-dose 6-MP inhibited these adaptable cells to a greater extent than it inhibited parental cells. Specifically, 6-MP inhibited progenitor-like cancer cells from proliferating thus keeping them arrested in reversible quiescence. Our results suggest that safe and effective drugs like 6-MP could halt progression of poor-prognosis MRD toward recurrence/metastasis. Supported by a State of Texas Grant for Rare and Aggressive Cancers. Citation Format: Balraj Singh, Vanessa N. Sarli, Anthony Lucci. Evaluation of 6-mercaptopurine in a cell culture model of adaptable triple-negative breast cancer with metastatic potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2003.