IIGM - Italian Institute for Genomic Medicine, c/o IRCSS, Candiolo, Italy.
Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy.
Cell Death Differ. 2021 Jul;28(7):2060-2082. doi: 10.1038/s41418-020-00733-4. Epub 2021 Feb 2.
Cancer stem cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-CHK1 axis is debated. Here, we show that the RSR is efficient in primary CSCs from colorectal cancer (CRC-SCs), and describe unique roles for PARP1 and MRE11/RAD51. First, we demonstrated that PARP1 is upregulated in CRC-SCs resistant to several replication poisons and RSR inhibitors (RSRi). In these cells, PARP1 modulates replication fork speed resulting in low constitutive RS. Second, we showed that MRE11 and RAD51 cooperate in the genoprotection and mitosis execution of PARP1-upregulated CRC-SCs. These roles represent therapeutic vulnerabilities for CSCs. Indeed, PARP1i sensitized CRC-SCs to ATRi/CHK1i, inducing replication catastrophe, and prevented the development of resistance to CHK1i. Also, MRE11i + RAD51i selectively killed PARP1-upregulated CRC-SCs via mitotic catastrophe. These results provide the rationale for biomarker-driven clinical trials in CRC using distinct RSRi combinations.
癌症干细胞 (CSCs) 是驱动疾病发展、进展、复发和治疗耐药的肿瘤亚群，针对它们的靶点可以确保肿瘤的根除。CSCs 表现出异质性的复制应激 (RS)，但以 ATR-CHK1 轴为中心的 RSR 功能/相关性存在争议。在这里，我们表明 RSR 在结直肠癌细胞 (CRC-SCs) 的原代 CSCs 中是有效的，并描述了 PARP1 和 MRE11/RAD51 的独特作用。首先，我们证明了 PARP1 在对几种复制毒物和 RSRi 有耐药性的 CRC-SCs 中上调。在这些细胞中，PARP1 调节复制叉速度，导致低组成性 RS。其次，我们表明 MRE11 和 RAD51 合作保护 PARP1 上调的 CRC-SCs 的基因组完整性并执行有丝分裂。这些作用代表了 CSCs 的治疗弱点。事实上，PARP1i 使 CRC-SCs 对 ATRi/CHK1i 敏感，诱导复制危机，并防止对 CHK1i 的耐药性发展。此外，MRE11i+RAD51i 通过有丝分裂灾难选择性杀死 PARP1 上调的 CRC-SCs。这些结果为使用不同的 RSRi 组合在 CRC 中进行基于生物标志物的临床试验提供了依据。
