MTOR促进癌症的适应性进化机制 作者： 发布时间：/6/5 16:32:50 澳大利亚加万医学研究所金霍恩癌症中心David M. Thomas研究组近日取得一项新成果。他们发现雷帕霉素（MTOR）信号可协调应激诱导的突变（SIM），促进癌症的适应性进化。6月5日《科学》杂志发表了这一成果。
他们在非遗传毒性药物选择下，在人类癌症的多个体外和体内模型中描述SIM，自相矛盾地以竞争的内在适应性成本提高适应性。全基因组方法确定MTOR的机制靶点是在多种癌症类型和病情之间介导SIM的压力敏感变阻器。
这些观察结果与抗药性的两阶段模型一致，在该模型中，最初的遗传多样性快速扩张被固有的适应性处罚所抵消，随后正常化以在新条件下完全适应。该模型提出了合成致死策略，以最大程度降低对抗癌治疗的抵抗力。
据了解，在微生物中，进化保守的机制通过SIM促进了对恶劣条件的适应。 类似过程可能是人类癌症进展和治疗失败的基础。
附：英文原文
Title: MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer
Author: Arcadi Cipponi, David L. Goode, Justin Bedo, Mark J. McCabe, Marina Pajic, David R. Croucher, Alvaro Gonzalez Rajal, Simon R. Junankar, Darren N. Saunders, Pavel Lobachevsky, Anthony T. Papenfuss, Danielle Nessem, Max Nobis, Sean C. Warren, Paul Timpson, Mark Cowley, Ana C. Vargas, Min R. Qiu, Daniele G. Generali, Shivakumar Keerthikumar, Uyen Nguyen, Niall M. Corcoran, Georgina V. Long, Jean-Yves Blay, David M. Thomas
Issue Volume: /06/05
Abstract: 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.
DOI: 10.1126/science.aau8768
Source:
期刊信息 Science：《科学》，创刊于1880年。隶属于美国科学促进会，最新IF：41.037官方网址：投稿链接：
