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 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.
Sharma
Sreenath V
SV
Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, MA 02129, USA.
Lee
Diana Y
DY
Li
Bihua
B
Quinlan
Margaret P
MP
Takahashi
Fumiyuki
F
Maheswaran
Shyamala
S
McDermott
Ultan
U
Azizian
Nancy
N
Zou
Lee
L
Fischbach
Michael A
MA
Wong
Kwok-Kin
KK
Brandstetter
Kathleyn
K
Wittner
Ben
B
Ramaswamy
Sridhar
S
Classon
Marie
M
Settleman
Jeff
J
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
D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human; D017526:Receptor, IGF Type 1