A chromatin-mediated reversible drug tolerant state in cancer cell subpopulations

By Sreenath V. Sharma, Diana Y. Lee, Bihua Li, M. P. Quinlan, F. Takahashi, S. Maheswaran, Ultan McDermott, N. Azizian, L. Zou, Michael A. Fischbach and 6 more. Cell, 2010

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SUMMARY Accumulating evidence implicates heterogeneity within cancer cell populations in the response to stressful exposures, including drug treatments. While modeling the acute response to various anti-cancer 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/908e03c066a36c2e98292517a97ba06e1fcb5c25

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Citations in the corpus

Transcriptional Addiction in Cancer (2017, neutral): “Treatment of tumor cells with various anti-cancer agents can select for populations of drug-tolerant cells that have become dependent on specific chromatin regulators such as histone demethylases (KDM5A) and deacetylases (HDACs) (Figure 6D) (Sharma et al., 2010).”
ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics (2014, methodology): “The newer third-generation EGFR TKIs that suppress T790M are showing remarkable progress in this subset of cancers (Ranson et al., 2013; Sequist et al., 2013a; Soria et al., 2013).”
Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized (2010, background): “Studies of other cell lines have suggested that therapy resistance can also reflect a reversible state (Sharma et al., 2010).”
Cancer epigenetics reaches mainstream oncology (2011, background): “A recent work connects the emergence of cancer cell resistance to the chemotherapeutic agent erlotinib with an increased expression of the HDM KDM5 (ref”
Cellular heterogeneity: when do differences make a difference? (2010, background): “…populations under carefully controlled laboratory conditions, the dynamics and responses of single cancer cells to drugs can vary widely (Cohen et al., 2008; Gascoigne and Taylor, 2008), and drug-tolerant states can arise transiently through reversible epigenetic changes (Sharma et al., 2010).”
Combination Epigenetic Therapy Has Efficacy in Patients with Refractory Advanced Non Small Cell Lung Cancer (2011, background): “Recent data from the Settleman laboratory have defined drug-resistant “persisters” within clonal cancer cell populations highly sensitive to targeted therapy and that maintenance of these drug-resistant persisters is epigenetically regulated (2).”
Epigenetic Determinants of Cancer. (2016, background): “Interestingly, preclinical studies have recently suggested that these drugs may be able to reprogram cancer cells in a way that reverses treatment resistance or sensitizes cancers to conventional chemotherapy and newer targeted therapies (Sharma et al. 2010).”