AsianScientist (Dec. 3, 2015) – Tumor cells can enlist the help of leukemia stem cells to fight back against a promising class of cancer drugs known as BET inhibitors (I-BET). These findings, by researchers from Melbourne’s Peter MacCallum Cancer Center, have been published in Nature.
BETs are a family of four proteins characterized by structures known as bromodomains. Bromodomains bind to a specific epigenetic mark (lysine acetylation) on histones, and the interaction in turn acts as a ‘meeting point’ for other epigenetic factors to join in and alter the surrounding chromatin environment. This could aberrantly influence the transcription rates on genes involved in cell proliferation, and BETs have indeed been linked to oncogenesis.
By targeting bromodomains and disrupting their interaction with chromatin, I-BETs have shown encouraging efficacies in suppressing tumor growth, most notably a highly aggressive form called acute myeloid leukemia (AML). However, little is known if and how cancer cells might fight back against the drug.
To answer this question, the research group of Professor Mark A. Dawson first generated AML cell lines by engineering oncogenic DNA constructs into hemotopoietic stem cells. These cells were exposed to increasing amounts of I-BET, and survivors from each treatment were isolated and cultured. They were shown through a number of tests to exhibit I-BET resistance, both in vitro and in vivo.
Using this cell model, the team then investigated causes of resistance. In classical drug resistance, resistant cells reduce the intake or actively eject the drug across the cell membrane. In this case, however, the researchers noticed that the resistant cells instead expressed fewer cell surface markers than I-BET sensitive cells.
Since cell surface markers are reflective of different cell lineages during differentiation, the authors reasoned that leukemia stem cells (LSCs) might be present in the resistant cell population. The found that LSCs were indeed higher in patient samples and that the enrichment of LSCs appeared driven only by sustained I-BET exposure.
When the transcriptomes of I-BET sensitive and resistant cells were compared, the Wnt/β-catenin pathway was found strongly expressed in resistant cells. The scientists then engineered the resistant cells to over-express Dkk1, a pathway inhibitor. This helped to re-establish cell sensitivity to I-BET. Thus, targeting Dkk1 could be a possible solution against the challenge of resistance, at least for I-BET.
The article can be found at: Fong et al. (2015) BET Inhibitor Resistance Emerges from Leukaemia Stem Cells.
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