A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations

被引：1908

作者：

Sharma, Sreenath V. ^{[1
]}

Lee, Diana Y. ^{[1
]}

Li, Bihua ^{[1
]}

Quinlan, Margaret P. ^{[1
]}

Takahashi, Fumiyuki ^{[1
]}

Maheswaran, Shyamala ^{[1
]}

McDermott, Ultan ^{[1
]}

Azizian, Nancy ^{[1
]}

Zou, Lee ^{[1
]}

Fischbach, Michael A. ^{[1
]}

Wong, Kwok-Kin ^{[2
]}

Brandstetter, Kathleyn ^{[2
]}

Wittner, Ben ^{[1
]}

Ramaswamy, Sridhar ^{[1
]}

Classon, Marie ^{[1
]}

Settleman, Jeff ^{[1
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA

[2] Dana Farber Canc Inst, Boston, MA 02115 USA

来源：

CELL | 2010年 / 141卷 / 01期

关键词：

STEM-CELLS; THERAPEUTIC RESISTANCE; HISTONE MODIFICATION; GROWTH; INSULIN; MECHANISMS; SENSITIVITY; RETREATMENT; INHIBITORS; DISEASE;

D O I：

10.1016/j.cell.2010.02.027

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：69 / 80

页数：12

共 42 条

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