Cancer cells enter a reversible drug-tolerant persister (DTP) state to evade death from chemotherapy and targeted agents. It is increasingly appreciated that DTPs are important drivers of therapy failure and tumor relapse. We combined cellular barcoding and mathematical modeling in patient-derived colorectal cancer models to identify and characterize DTPs in response to chemotherapy. Barcode analysis revealed no loss of clonal complexity of tumors that entered the DTP state and recurred following treatment cessation. Our data fit a mathematical model where all cancer cells, and not a small subpopulation, possess an equipotent capacity to become DTPs. Mechanistically, we determined that DTPs display remarkable transcriptional and functional similarities to diapause, a reversible state of suspended embryonic development triggered by unfavorable environmental conditions. Our study provides insight into how cancer cells use a developmentally conserved mechanism to drive the DTP state, pointing to novel therapeutic opportunities to target DTPs.

癌细胞进入可逆的耐药持续状态（DTP），以逃避化疗和靶向药物的死亡。人们越来越认识到 DTP 是治疗失败和肿瘤复发的重要驱动因素。我们在源自患者的结直肠癌模型中结合了细胞条形码和数学模型，以识别和表征化疗反应中的 DTP。条形码分析显示，进入 DTP 状态并在治疗停止后复发的肿瘤的克隆复杂性没有损失。我们的数据符合一个数学模型，其中所有癌细胞（而不是一小部分细胞）都具有成为 DTP 的同等能力。从机制上讲，我们确定 DTP 在转录和功能上与滞育具有显着的相似性，滞育是一种由不利环境条件引发的胚胎发育暂停的可逆状态。我们的研究深入了解了癌细胞如何利用发育上保守的机制来驱动 DTP 状态，并指出了针对 DTP 的新治疗机会。