Inhibition of Ataxia-Telangiectasia Mutated and RAD3-Related (ATR) Overcomes Oxaliplatin Resistance and Promotes Antitumor Immunity in Colorectal Cancer
Inhibition of Ataxia-Telangiectasia Mutated and RAD3-Related (ATR) Overcomes Oxaliplatin Resistance and Promotes Antitumor Immunity in Colorectal Cancer
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DOI：
10.1158/0008-5472.can-18-2807
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发表时间：
2019-06-01
期刊：
影响因子：
11.2
通讯作者：
Gongora, Celine
中科院分区：
文献类型：
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作者：
Combes, Eve;Andrade, Augusto F.;Gongora, Celine
尽管许多结直肠癌患者最初对化疗药物奥沙利铂有反应，但对这种治疗的获得性耐药性仍然是这种疾病长期管理的主要挑战。为了确定结直肠癌奥沙利铂耐药的分子靶点，我们使用激酶组文库进行了基于shRNA的功能丧失遗传筛选。我们发现，沉默共济失调毛细血管扩张突变和RAD 3相关（ATR），丝氨酸/苏氨酸蛋白激酶参与DNA应激反应，恢复奥沙利铂耐药的细胞模型中的奥沙利铂敏感性。联合应用ATR抑制剂VE-822和奥沙利铂在6种不同的结直肠癌细胞系及其奥沙利铂耐药亚克隆中产生了强烈的协同作用，促进了DNA单链和双链断裂形成、生长停滞和凋亡。这种处理还增加了复制应激、细胞质DNA以及与免疫原性细胞死亡相关的信号，例如钙网蛋白暴露以及HMGB 1和ATP释放。在同系结直肠癌小鼠模型中，VE-822和奥沙利铂联合给药通过促进抗肿瘤T细胞应答显著增加存活率。最后，一个DNA修复基因标记区分了敏感的耐药结直肠癌患者。总体而言，我们的研究结果强调了ATR抑制联合奥沙利铂使细胞对化疗敏感的潜力，作为结直肠癌患者的治疗选择。重要性：这些发现表明，大肠癌细胞对奥沙利铂的耐药性可以通过ATR抑制剂克服，并且两种药物的联合治疗发挥协同抗肿瘤作用。
Although many patients with colorectal cancer initially respond to the chemotherapeutic agent oxaliplatin, acquired resistance to this treatment remains a major challenge to the long-term management of this disease. To identify molecular targets of oxaliplatin resistance in colorectal cancer, we performed an shRNA-based loss-of-function genetic screen using a kinome library. We found that silencing of ataxia-telangiectasia mutated and RAD3-related (ATR), a serine/ threonine protein kinase involved in the response to DNA stress, restored oxaliplatin sensitivity in a cellular model of oxaliplatin resistance. Combined application of the ATR inhibitor VE-822 and oxaliplatin resulted in strong synergistic effects in six different colorectal cancer cell lines and their oxaliplatin-resistant subclones, promoted DNA single-and double-strand break formation, growth arrest, and apoptosis. This treatment also increased replicative stress, cytoplasmic DNA, and signals related to immunogenic cell death such as calreticulin exposure and HMGB1 and ATP release. In a syngeneic colorectal cancer mouse model, combined administration of VE-822 and oxaliplatin significantly increased survival by promoting antitumor T-cell responses. Finally, a DNA repair gene signature discriminated sensitive from drug-resistant patients with colorectal cancer. Overall, our results highlight the potential of ATR inhibition combined with oxaliplatin to sensitize cells to chemotherapy as a therapeutic option for patients with colorectal cancer. Significance: These findings demonstrate that resistance to oxaliplatin in colorectal cancer cells can be overcome with inhibitors of ATR and that combined treatment with both agents exerts synergistic antitumor effects.