A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations

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...

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Podrobná bibliografie
Vydáno v:	Cell Ročník 141; číslo 1; s. 69
Hlavní autoři:	Sharma, Sreenath V, Lee, Diana Y, Li, Bihua, Quinlan, Margaret P, Takahashi, Fumiyuki, Maheswaran, Shyamala, McDermott, Ultan, Azizian, Nancy, Zou, Lee, Fischbach, Michael A, Wong, Kwok-Kin, Brandstetter, Kathleyn, Wittner, Ben, Ramaswamy, Sridhar, Classon, Marie, Settleman, Jeff
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 02.04.2010
Témata:	Cell Line, Tumor Chromatin - metabolism Chromatin - pathology DNA Damage Drug Resistance, Neoplasm Histone Deacetylase Inhibitors - pharmacology Histone Demethylases - metabolism Humans Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors Jumonji Domain-Containing Histone Demethylases - genetics Jumonji Domain-Containing Histone Demethylases - metabolism Neoplasms - drug therapy Neoplasms - metabolism Neoplasms - pathology Receptor, IGF Type 1 - metabolism
ISSN:	1097-4172, 1097-4172
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4172 1097-4172
DOI:	10.1016/j.cell.2010.02.027