Evaluation of 6-mercaptopurine in a cell culture model of adaptable triple-negative breast cancer with metastatic potential
Metrics: PDF 1027 views | Full Text 3121 views | ?
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
|Anthony Lucci,||email:||[email protected]|
|Balraj Singh,||email:||[email protected]|
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.