MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer

doi:10.1126/science.aau8768

GSTDTAP > 气候变化

DOI	10.1126/science.aau8768
	MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer
	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
	2020-06-05
发表期刊	Science
出版年	2020
英文摘要	Bacteria adapt to harsh conditions such as antibiotic exposure by acquiring new mutations, a process called stress-induced mutagenesis. Cipponi et al. investigated whether similar programs of mutagenesis play a role in the response of cancer cells to targeted therapies. Using in vitro models of intense drug selection and genome-wide functional screens, the authors found evidence for an analogous process in cancer and showed that it is regulated by the mammalian target of rapamycin (mTOR) signaling pathway. This pathway appears to mediate a stress-related switch to error-prone DNA repair, resulting in the generation of mutations that facilitate the emergence of drug resistance. Science , this issue p. [1127][1] 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. [1]: /lookup/doi/10.1126/science.aau8768
领域	气候变化 ; 资源环境
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引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/273447
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Arcadi Cipponi,David L. Goode,Justin Bedo,et al. MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer[J]. Science,2020.
APA	Arcadi Cipponi.,David L. Goode.,Justin Bedo.,Mark J. McCabe.,Marina Pajic.,...&David M. Thomas.(2020).MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer.Science.
MLA	Arcadi Cipponi,et al."MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer".Science (2020).