[HTML][HTML] A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations
SV Sharma, DY Lee, B Li, MP Quinlan, F Takahashi… - Cell, 2010 - cell.com
SV Sharma, DY Lee, B Li, MP Quinlan, F Takahashi, S Maheswaran, U McDermott…
Cell, 2010•cell.comAccumulating evidence implicates heterogeneity within cancer cell populations in the
response to stressful exposures, including drug treatments. While modeling the acute
response to various anticancer agents in drug-sensitive human tumor cell lines, we
consistently detected a small subpopulation of reversibly" drug-tolerant" cells. These cells
demonstrate> 100-fold reduced drug sensitivity and maintain viability via engagement of IGF-
1 receptor signaling and an altered chromatin state that requires the histone demethylase …
response to stressful exposures, including drug treatments. While modeling the acute
response to various anticancer agents in drug-sensitive human tumor cell lines, we
consistently detected a small subpopulation of reversibly" drug-tolerant" cells. These cells
demonstrate> 100-fold reduced drug sensitivity and maintain viability via engagement of IGF-
1 receptor signaling and an altered chromatin state that requires the histone demethylase …
Summary
Accumulating evidence implicates heterogeneity within cancer cell populations in the response to stressful exposures, including drug treatments. While modeling the acute response to various anticancer agents in drug-sensitive human tumor cell lines, we consistently detected a small subpopulation of reversibly "drug-tolerant" cells. These cells demonstrate >100-fold reduced drug sensitivity and maintain viability via engagement of IGF-1 receptor signaling and an altered chromatin state that requires the histone demethylase RBP2/KDM5A/Jarid1A. This drug-tolerant phenotype is transiently acquired and relinquished at low frequency by individual cells within the population, implicating the dynamic regulation of phenotypic heterogeneity in drug tolerance. The drug-tolerant subpopulation can be selectively ablated by treatment with IGF-1 receptor inhibitors or chromatin-modifying agents, potentially yielding a therapeutic opportunity. Together, these findings suggest that cancer cell populations employ a dynamic survival strategy in which individual cells transiently assume a reversibly drug-tolerant state to protect the population from eradication by potentially lethal exposures.
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