A Chromatin-mediated Reversible Drug-tolerant State in Cancer Cell Subpopulations

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2010 Apr 8

PMID 20371346

Citations 1347

Authors

Sreenath V Sharma

Diana Y Lee

Bihua Li

Margaret P Quinlan

Fumiyuki Takahashi

Shyamala Maheswaran

Ultan McDermott

Nancy Azizian

Lee Zou

Michael A Fischbach

Kwok-Kin Wong

Kathleyn Brandstetter

Ben Wittner

Sridhar Ramaswamy

Marie Classon

Jeff Settleman

Affiliations

Soon will be listed here.

Abstract

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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