Triple negative breast cancer (TNBC) is an aggressive type of cancer that is known to be resistant to radiotherapy (RT). Evidence is accumulating that is indicative of the plasticity of TNBC, where one cancer subtype switches to another in response to various treatments, including RT. In this study we aim to overcome tumor resistance by designing TNBC-sensitizing targeted therapies that exploit the plasticity occurring due to radiation exposure. Using single cell analysis of molecular changes occurring in irradiated TNBC tumors, we identified two initially undetected distinct subpopulations, represented by overexpressed Her2 and cMet, expanding post-RT and persisting in surviving tumors. Using murine cancer models and patient-derived TNBC tumors, we showed that only simultaneous targeting of Her2 and cMet was successful in sensitizing TNBC to RT and preventing its regrowth. The strategy presented herein holds the potential to be broadly applicable in clinical use.

中文翻译：

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在三阴性乳腺癌肿瘤中绘制细胞亚群的图谱可为癌症对放射疗法的敏感性提供工具

三阴性乳腺癌（TNBC）是一种侵略性癌症，已知对放射疗法（RT）有抵抗力。越来越多的证据表明，TNBC是可塑性的，其中一种癌症亚型在响应包括RT在内的各种治疗后会转变为另一种。在这项研究中，我们旨在通过设计TNBC敏化靶向疗法来克服肿瘤抵抗力，该疗法利用了由于辐射暴露而产生的可塑性。通过对照射的TNBC肿瘤中发生的分子变化进行单细胞分析，我们鉴定了两个最初未检测到的不同亚群，以过表达的Her2和cMet为代表，它们在RT后扩展并在存活的肿瘤中持续存在。利用鼠类癌症模型和患者来源的TNBC肿瘤，我们显示只有同时靶向Her2和cMet才能成功使TNBC对RT敏感并阻止其再生。本文介绍的策略具有广泛应用于临床的潜力。