据科学家在2月17日Cell上的报道，抑制通过延伸染色体两端的保护帽从破坏中抢救恶性细胞的端粒酶，杀死肿瘤细胞但也触发引起癌症存活和传播的耐药性通路。
端粒酶在许多晚期癌症中过度表达，但是评价它作为治疗靶标的潜力要求我们理解它做什么且它如何做。
我们利用小鼠的实验性优点来造模，并更精确地研究在癌症发育、进展和治疗中的端粒危机、端粒酶复活和端粒酶消除。这个精巧的模型揭示了两种机制，包括一种被癌细胞用于适应端粒酶丧失的意料之外的代谢通路。
这些发现让我们预期肿瘤细胞可能对端粒酶抑制怎样反应，突出开发靶向端粒酶和这些适应性耐药机制的药物联合的需要。
研究人员用实验对端粒酶作为治疗靶标进行了评估。在正常细胞中，端粒酶活性性或缺失，正常细胞在染色体末端有细胞分裂期间保护DNA稳定性的称为调聚物的重复核苷酸片段。
随首每一次分裂端粒变短，最后导致基因组不稳定和细胞死亡，术称"端粒危机"。在癌症中，端粒酶在端粒危机期间变得活跃并通过延长端粒抢救基因组上异常的细胞。（生物谷bioon.com）
doi:10.1016/j.cell.2011.12.028
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Antitelomerase Therapy Provokes ALT and Mitochondrial Adaptive Mechanisms in Cancer
Jian Hu,Soyoon Sarah Hwang,Marc Liesa,Boyi Gan,Ergun Sahin,Mariela Jaskelioff,Zhihu Ding,Haoqiang Ying,Adam T. Boutin,Hailei Zhang,Shawn Johnson,Elena Ivanova,Maria Kost-Alimova,Alexei Protopopov,Yaoqi Alan Wang,Orian S. Shirihai,Lynda Chin,Ronald A. DePinho
Summary To assess telomerase as a cancer therapeutic target and determine adaptive mechanisms to telomerase inhibition, we modeled telomerase reactivation and subsequent extinction in T cell lymphomas arising in Atm?/?mice engineered with an inducible telomerase reverse transcriptase allele. Telomerase reactivation in the setting of telomere dysfunction enabled full malignant progression with alleviation of telomere dysfunction-induced checkpoints. These cancers possessed copy number alterations targeting key loci in human T cell lymphomagenesis. Upon telomerase extinction, tumor growth eventually slowed with reinstatement of telomere dysfunction-induced checkpoints, yet growth subsequently resumed as tumors acquired alternative lengthening of telomeres (ALT) and aberrant transcriptional networks centering on mitochondrial biology and oxidative defense. ALT+ tumors acquired amplification/overexpression of PGC-1β, a master regulator of mitochondrial biogenesis and function, and they showed marked sensitivity to PGC-1β or SOD2 knockdown. Genetic modeling of telomerase extinction reveals vulnerabilities that motivate coincidental inhibition of mitochondrial maintenance and oxidative defense mechanisms to enhance antitelomerase cancer therapy.
