美国杜克大学Kris C. Wood、法国巴黎大学Alexandre Puissant等研究人员合作，利用拮抗多效性设计出化疗诱导的进化陷阱从而靶向癌症耐药性。相关论文于2020年3月16日在线发表于《自然—遗传学》。
研究人员表示，局部适应通过获得正向选择特征，将种群引导至环境特定的最佳适应性。但是，快速的环境变化可以识别隐藏的适应性权衡，从而使适应性转变为适应不良，进而导致进化陷阱。癌症，是一种容易产生耐药性的疾病，原则上容易受到这种陷阱的影响。
因此，研究人员在经过各种化学疗法处理的急性髓细胞白血病（AML）细胞中进行了CRISPR-Cas9组合筛选，以绘制适应性权衡的药物依赖性遗传基础，这一概念被称为拮抗多效性（AP）。
他们将PRC2-NSD2/3介导的MYC调控轴确定为药物诱导的AP途径，其可赋予对溴结构域抑制的抗性和对BCL-2抑制的敏感性，从而作为一种进化陷阱。在不同的AML细胞系和患者来源的异种移植模型中，研究人员发现通过该途径获得的对溴结构域抑制抗性同时也暴露了对BCL-2抑制的超敏反应。因此，可以利用药物诱导的AP可用于设计进化陷阱，从而选择性靶向肿瘤中的耐药性。
附：英文原文
Title: Using antagonistic pleiotropy to design a chemotherapy-induced evolutionary trap to target drug resistance in cancer
Author: Kevin H. Lin, Justine C. Rutter, Abigail Xie, Bryann Pardieu, Emily T. Winn, Reinaldo Dal Bello, Antoine Forget, Raphael Itzykson, Yeong-Ran Ahn, Ziwei Dai, Raiyan T. Sobhan, Grace R. Anderson, Katherine R. Singleton, Amy E. Decker, Peter S. Winter, Jason W. Locasale, Lorin Crawford, Alexandre Puissant, Kris C. Wood
Issue&Volume: 2020-03-16
Abstract: Local adaptation directs populations towards environment-specific fitness maxima through acquisition of positively selected traits. However, rapid environmental changes can identify hidden fitness trade-offs that turn adaptation into maladaptation, resulting in evolutionary traps. Cancer, a disease that is prone to drug resistance, is in principle susceptible to such traps. We therefore performed pooled CRISPR–Cas9 knockout screens in acute myeloid leukemia (AML) cells treated with various chemotherapies to map the drug-dependent genetic basis of fitness trade-offs, a concept known as antagonistic pleiotropy (AP). We identified a PRC2–NSD2/3-mediated MYC regulatory axis as a drug-induced AP pathway whose ability to confer resistance to bromodomain inhibition and sensitivity to BCL-2 inhibition templates an evolutionary trap. Across diverse AML cell-line and patient-derived xenograft models, we find that acquisition of resistance to bromodomain inhibition through this pathway exposes coincident hypersensitivity to BCL-2 inhibition. Thus, drug-induced AP can be leveraged to design evolutionary traps that selectively target drug resistance in cancer.
DOI: 10.1038/s41588-020-0590-9
Source: https://www.nature.com/articles/s41588-020-0590-9
Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex
本期文章：《自然—遗传学》：Online/在线发表
