Evaluation of 6-mercaptopurine in a cell culture model of adaptable triple-negative breast cancer with metastatic potential
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Balraj Singh1,2, Vanessa N. Sarli1,2, Hannah E. Kinne1,2, Anna Shamsnia1,2 and Anthony Lucci1,2
1 Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2 Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Keywords: cancer evolution; metabolic adaptability in cancer; inflammatory breast cancer; minimal residual disease; TET2
Received: September 29, 2018 Accepted: May 13, 2019 Published: June 04, 2019
Progenitor-like cancer cells that can survive in reversible quiescence when faced with various challenges in the body are often behind disease progression. A lack of glutamine in culture medium, which eliminates >99.9% of proliferating SUM149 triple-negative breast cancer cells, selects such adaptable, pan-resistant cells. 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. Our data suggesting that highly adaptable cells are generated through reprograming of the epigenome and transcriptome led us to evaluate low-dose 6-mercaptopurine as a potential therapy in our model. We found that a long treatment with low-dose 6-mercaptopurine inhibited the proliferation of these adaptable cells to a greater extent than it inhibited parental cells. Importantly, a small percentage of adaptable cells survived a low-dose 6-mercaptopurine treatment in a reversible quiescence, analogous to the persistence of abnormal progenitor-like cells in inflammatory bowel disease, which stays in a durable remission with a 6-mercaptopurine treatment. Based on a biomarkers analysis, a long treatment with 6-mercaptopurine or aspirin partially reversed epithelial to mesenchymal transition in adaptable cancer cells. A cell culture model of adaptable cancer cells that persist in the body will help in discovering superior therapies that can be offered before the disease advances to metastasis.
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