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.