A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.
A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.
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DOI：
10.1016/j.cell.2010.02.027
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发表时间：
2010-04-02
期刊：
影响因子：
64.5
通讯作者：
Settleman J
中科院分区：
文献类型：
--
作者：
Sharma SV;Lee DY;Li B;Quinlan MP;Takahashi F;Maheswaran S;McDermott U;Azizian N;Zou L;Fischbach MA;Wong KK;Brandstetter K;Wittner B;Ramaswamy S;Classon M;Settleman J
越来越多的证据表明，癌细胞群体对压力暴露（包括药物治疗）的反应具有异质性。在对药物敏感的人肿瘤细胞系中对各种抗癌剂的急性反应进行建模时，我们始终检测到一小部分可逆性“耐药”细胞。这些细胞表现出>100倍的药物敏感性降低，并通过参与IGF-1受体信号传导和改变染色质状态来维持活力，这需要组蛋白脱甲基酶RBP 2/KDM 5A/Jarid 1A。这种耐药表型是短暂获得和放弃在低频率的人口中的个别细胞，涉及动态调节的表型异质性的药物耐受性。药物耐受性亚群可以通过IGF-1受体抑制剂或染色质修饰剂治疗选择性消融，可能产生治疗机会。总之，这些发现表明，癌细胞群体采用动态生存策略，其中单个细胞短暂地呈现可逆的药物耐受状态，以保护群体免受潜在致命暴露的根除。
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.
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