Radiation therapy (RT) is one of the most commonly used anticancer therapies. However, the landscape of cellular response to irradiation, especially to a single high-dose irradiation, remains largely unknown. In this study, we performed a whole-genome CRISPR loss-of-function screen and revealed temporal inherent and acquired responses to RT. Specifically, we found that loss of the IL1R1 pathway led to cellular resistance to RT. This is in part because of the involvement of radiation-induced IL1R1-dependent transcriptional regulation, which relies on the NF-κB pathway. Moreover, the mitochondrial anti-apoptotic pathway, particularly the BCL2L1 gene, is crucially important for cell survival after radiation. BCL2L1 inhibition combined with RT dramatically impeded tumor growth in several breast cancer cell lines and syngeneic models. Taken together, our results suggest that the combination of an apoptosis inhibitor such as a BCL2L1 inhibitor with RT may represent a promising anticancer strategy for solid cancers including breast cancer.

中文翻译：

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全基因组 CRISPR 筛选揭示了 BCL2L1 抑制和放射治疗之间的综合致死率。

放射治疗（RT）是最常用的抗癌疗法之一。然而，细胞对辐射的反应，特别是对单次高剂量辐射的反应，在很大程度上仍然未知。在这项研究中，我们进行了全基因组 CRISPR 功能丧失筛选，并揭示了对 RT 的时间固有反应和获得​​性反应。具体来说，我们发现 IL1R1 通路的缺失会导致细胞对 RT 的抵抗。这部分是因为辐射诱导的 IL1R1 依赖性转录调控的参与，该转录调控依赖于 NF-κB 通路。此外，线粒体抗凋亡途径，特别是 BCL2L1 基因，对于辐射后细胞的存活至关重要。 BCL2L1 抑制与 RT 相结合可显着抑制多种乳腺癌细胞系和同基因模型中的肿瘤生长。综上所述，我们的结果表明，细胞凋亡抑制剂（例如 BCL2L1 抑制剂）与 RT 的组合可能是治疗包括乳腺癌在内的实体癌的一种有前途的抗癌策略。