title: A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.
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.
authors.affiliation: Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, MA 02129, USA.
authors.forename: Sreenath V
authors.initials: SV
authors.lastname: Sharma
authors.forename: Diana Y
authors.initials: DY
authors.lastname: Lee
authors.forename: Bihua
authors.initials: B
authors.lastname: Li
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Quinlan
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Takahashi
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.forename: Nancy
authors.initials: N
authors.lastname: Azizian
authors.forename: Lee
authors.initials: L
authors.lastname: Zou
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fischbach
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Kathleyn
authors.initials: K
authors.lastname: Brandstetter
authors.forename: Ben
authors.initials: B
authors.lastname: Wittner
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: Marie
authors.initials: M
authors.lastname: Classon
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D056466:Histone Demethylases / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D017526:Receptor, IGF Type 1 / Q000378:metabolism
chemical_list: D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human; D017526:Receptor, IGF Type 1