MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer
MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer
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DOI：
10.1126/science.aau8768
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发表时间：
2020-06-05
期刊：
影响因子：
56.9
通讯作者：
Thomas, David M.
中科院分区：
文献类型：
--
作者：
Cipponi, Arcadi;Goode, David L.;Thomas, David M.
在微生物中，进化上保守的机制通过应激诱导突变(SIM)促进对恶劣条件的适应。类似的过程可能是人类癌症进展和治疗失败的基础。我们描述了在非遗传毒性药物选择下的多种体外和体内人类癌症模型中的SIM，矛盾地增强了适应性，但竞争的内在适应成本。一种全基因组方法确定了雷帕霉素(MTOR)的机制靶点，它是一种应力敏感变阻器，在多种癌症类型和条件下介导SIM。这些观察结果与耐药性的两阶段模型是一致的，在该模型中，遗传多样性最初的快速扩张被内在的适应度惩罚所抵消，随后正常化，以在新的条件下完全适应。这个模型建议了合成致命策略，以最大限度地减少对抗癌治疗的抵抗。
In microorganisms, evolutionarily conserved mechanisms facilitate adaptation to harsh conditions through stress-induced mutagenesis (SIM). Analogous processes may underpin progression and therapeutic failure in human cancer. We describe SIM in multiple in vitro and in vivo models of human cancers under nongenotoxic drug selection, paradoxically enhancing adaptation at a competing intrinsic fitness cost. A genome-wide approach identified the mechanistic target of rapamycin (MTOR) as a stress-sensing rheostat mediating SIM across multiple cancer types and conditions. These observations are consistent with a two-phase model for drug resistance, in which an initially rapid expansion of genetic diversity is counterbalanced by an intrinsic fitness penalty, subsequently normalizing to complete adaptation under the new conditions. This model suggests synthetic lethal strategies to minimize resistance to anticancer therapy.