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

SummaryAccumulating 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.PaperClip To listen to this audio, enable JavaScript on your browser. However, you can download and play the audio by clicking on the icon belowHelp with MP3 filesOptionsDownload audio (2490 K)

Graphical AbstractFigure optionsDownload high-quality image (153 K)Download as PowerPoint slideHighlights
► Human cancer cell lines harbor a subpopulation of “drug-tolerant” cells
► The drug-tolerant state can emerge de novo and is transiently maintained
► The emergence of drug tolerance requires IGF-1R signaling
► Drug tolerance involves distinct chromatin states that can be disrupted