Targeting the DNA Damage Response Pathways and Replication Stress in Colorectal Cancer.
Targeting the DNA Damage Response Pathways and Replication Stress in Colorectal Cancer.
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DOI：
10.1158/1078-0432.ccr-22-0875
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发表时间：
2022-09-01
影响因子：
11.5
通讯作者：
Arena, Sabrina
中科院分区：
文献类型：
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作者：
Durinikova, Erika;Reilly, Nicole M.;Buzo, Kristi;Mariella, Elisa;Chila, Rosaria;Lorenzato, Annalisa;Dias, Joao M. L.;Grasso, Gaia;Pisati, Federica;Lamba, Simona;Corti, Giorgio;Degasperi, Andrea;Cancelliere, Carlotta;Mauri, Gianluca;Andrei, Pietro;Linnebacher, Michael;Marsoni, Silvia;Siena, Salvatore;Sartore-Bianchi, Andrea;Nik-Zainal, Serena;Di Nicolantonio, Federica;Bardelli, Alberto;Arena, Sabrina
基因组不稳定性是癌症的标志，靶向DNA损伤反应（DDR）正在成为不同实体瘤中有前途的治疗策略。靶向DDR在结直肠癌中的有效性尚未得到广泛探讨。我们用ATM、ATR、CHK 1、WEE 1和DNA-PK抑制剂与化疗药物平行挑战了112个细胞模型，这些模型重现了转移性结直肠癌的基因组景观。然后，我们将重点放在ATR抑制剂（ATRi）上，为了确定反应和耐药性的假定生物标志物，我们在多个水平上分析了对这些药物高度敏感或耐药的结直肠癌模型。我们发现，大约30%的结直肠癌，包括携带KRAS和BRAF突变且对靶向药物无反应的结直肠癌，对至少一种DDR抑制剂敏感。通过研究对ATRi反应的潜在生物标志物，我们发现ATRi敏感细胞在基础水平显示磷酸化RPA 32灶减少，而ATRi抗性细胞在复制应激反应中显示RAD 51灶形成增加。ATM和RAD 51 C表达的缺乏与ATRi敏感性相关。突变签名和HRDetect评分的分析鉴定了ATRI敏感模型的亚组。来自转移性结直肠癌患者的类器官概括了在细胞系中获得的发现。总之，目前治疗难治性结直肠癌的一个子集可以受益于DDR途径和复制应激的抑制剂。涉及磷酸化RPA 32和RAD 51病灶、ATM和RAD 51 C表达缺乏以及突变特征分析的复合生物标志物可用于鉴定可能对ATRi有反应的结直肠癌。
Genomic instability is a hallmark of cancer and targeting DNA damage response (DDR) is emerging as a promising therapeutic strategy in different solid tumors. The effectiveness of targeting DDR in colorectal cancer has not been extensively explored. We challenged 112 cell models recapitulating the genomic landscape of metastatic colorectal cancer with ATM, ATR, CHK1, WEE1, and DNA-PK inhibitors, in parallel with chemotherapeutic agents. We focused then on ATR inhibitors (ATRi) and, to identify putative biomarkers of response and resistance, we analyzed at multiple levels colorectal cancer models highly sensitive or resistant to these drugs. We found that around 30% of colorectal cancers, including those carrying KRAS and BRAF mutations and unresponsive to targeted agents, are sensitive to at least one DDR inhibitor. By investigating potential biomarkers of response to ATRi, we found that ATRi-sensitive cells displayed reduced phospho-RPA32 foci at basal level, while ATRi-resistant cells showed increased RAD51 foci formation in response to replication stress. Lack of ATM and RAD51C expression was associated with ATRi sensitivity. Analysis of mutational signatures and HRDetect score identified a subgroup of ATRi-sensitive models. Organoids derived from patients with metastatic colorectal cancer recapitulated findings obtained in cell lines. In conclusion, a subset of colorectal cancers refractory to current therapies could benefit from inhibitors of DDR pathways and replication stress. A composite biomarker involving phospho-RPA32 and RAD51 foci, lack of ATM and RAD51C expression, as well as analysis of mutational signatures could be used to identify colorectal cancers likely to respond to ATRi.