Sartori Giulio, Tarantelli Chiara, Spriano Filippo, Gaudio Eugenio, Cascione Luciano, Mascia Michele, Barreca Marilia, Arribas Alberto J, Licenziato Luca, Golino Gaetanina, Ferragamo Adele, Pileri Stefano, Damia Giovanna, Zucca Emanuele, Stathis Anastasios, Politz Oliver, Wengner Antje M, Bertoni Francesco
Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland.
SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Br J Haematol. 2024 Jan;204(1):191-205. doi: 10.1111/bjh.19218. Epub 2023 Nov 27.
The DNA damage response (DDR) is the cellular process of preserving an intact genome and is often deregulated in lymphoma cells. The ataxia telangiectasia and Rad3-related (ATR) kinase is a crucial factor of DDR in the response to DNA single-strand breaks. ATR inhibitors are agents that have shown considerable clinical potential in this context. We characterized the activity of the ATR inhibitor elimusertib (BAY 1895344) in a large panel of lymphoma cell lines. Furthermore, we evaluated its activity combined with the clinically approved PI3K inhibitor copanlisib in vitro and in vivo. Elimusertib exhibits potent anti-tumour activity across various lymphoma subtypes, which is associated with the expression of genes related to replication stress, cell cycle regulation and, as also sustained by CRISPR Cas9 experiments, CDKN2A loss. In several tumour models, elimusertib demonstrated widespread anti-tumour activity stronger than ceralasertib, another ATR inhibitor. This activity is present in both DDR-proficient and DDR-deficient lymphoma models. Furthermore, a combination of ATR and PI3K inhibition by treatment with elimusertib and copanlisib has in vitro and in vivo anti-tumour activity, providing a potential new treatment option for lymphoma patients.
DNA损伤反应（DDR）是维持基因组完整的细胞过程，在淋巴瘤细胞中常失调。共济失调毛细血管扩张症和Rad3相关（ATR）激酶是DDR中对DNA单链断裂作出反应的关键因素。ATR抑制剂在这方面已显示出相当大的临床潜力。我们在一大组淋巴瘤细胞系中表征了ATR抑制剂艾力穆塞替布（BAY 1895344）的活性。此外，我们在体外和体内评估了其与临床批准的PI3K抑制剂库潘尼西联合使用时的活性。艾力穆塞替布在各种淋巴瘤亚型中均表现出强大的抗肿瘤活性，这与复制应激、细胞周期调控相关基因的表达有关，并且如CRISPR Cas9实验所证实的，也与CDKN2A缺失有关。在几个肿瘤模型中，艾力穆塞替布显示出比另一种ATR抑制剂西拉穆塞替布更广泛的抗肿瘤活性。这种活性在DDR功能正常和DDR缺陷的淋巴瘤模型中均存在。此外，通过艾力穆塞替布和库潘尼西联合治疗抑制ATR和PI3K具有体外和体内抗肿瘤活性，为淋巴瘤患者提供了一种潜在的新治疗选择。
