Journal
CELL
Volume 141, Issue 1, Pages 69-80Publisher
CELL PRESS
DOI: 10.1016/j.cell.2010.02.027
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Funding
- LUNGevity Foundation
- Goldman Philanthropic
- NIH [RO1CA115830, P20 CA090578]
- NATIONAL CANCER INSTITUTE [P50CA090578, P20CA090578, R01CA115830] Funding Source: NIH RePORTER
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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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