Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer.
Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer.
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DOI：
10.1158/1078-0432.ccr-20-3316
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发表时间：
2021-04-01
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影响因子：
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通讯作者：
Szallasi Z
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作者：
Börcsök J;Sztupinszki Z;Bekele R;Gao SP;Diossy M;Samant AS;Dillon KM;Tisza V;Spisák S;Rusz O;Csabai I;Pappot H;Frazier ZJ;Konieczkowski DJ;Liu D;Vasani N;Rodrigues JA;Solit DB;Hoffman-Censits JH;Plimack ER;Rosenberg JE;Lazaro JB;Taplin ME;Iyer G;Brunak S;Lozsa R;Van Allen EM;Szüts D;Mouw KW;Szallasi Z
基于顺铂的化疗是肌肉浸润性和转移性尿路上皮癌的一线治疗方法。大约 10% 的膀胱尿路上皮肿瘤的核苷酸切除修复 (NER) 基因 ERCC2 存在体细胞错义突变，这使得对顺铂化疗的敏感性增加。然而，由于医疗禁忌症，很大一部分患者不适合接受基于顺铂的治疗，并且对于不适合铂类或铂类难治性 ERCC2 突变病例，没有 NER 靶向方法可用。我们使用了一系列 NER 充足和 NER 缺乏的临床前肿瘤模型来测试对罗氟芬（一种废弃的抗癌药物）的敏感性。此外，我们使用来自多个尿路上皮肿瘤队列的可用临床和测序数据来开发和验证 ERCC2 缺陷和顺铂敏感性的复合突变特征。我们发现了肿瘤 NER 缺乏和对艾洛芬敏感性之间的一种新的综合致死关系。 Irofulven 专门针对转录偶联 NER (TC-NER) 通路失活的细胞，并在体外和体内产生强烈的反应，包括在获得性顺铂耐药的模型中，同时对具有完整 NER 的细胞影响最小。我们还发现，ERCC2 缺陷的复合突变特征与患者的顺铂反应密切相关，并且还与临床前模型中的顺铂和伊洛芬敏感性相关。肿瘤 NER 缺陷导致对 irofulven 的敏感性，irofulven 是一种以前被废弃的抗癌药物，在 NER 熟练细胞中活性极低。 NER 缺陷的复合突变特征可能有助于识别可能对 NER 靶向药物（包括顺铂和艾洛芬）产生反应的患者。
Cisplatin-based chemotherapy is a first-line treatment for muscle-invasive and metastatic urothelial cancer. Approximately 10% of bladder urothelial tumors have a somatic missense mutation in the nucleotide excision repair (NER) gene, ERCC2, which confers increased sensitivity to cisplatin-based chemotherapy. However, a significant subset of patients is ineligible to receive cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory ERCC2-mutant cases. We used a series of NER-proficient and NER-deficient preclinical tumor models to test sensitivity to irofulven, an abandoned anticancer agent. In addition, we used available clinical and sequencing data from multiple urothelial tumor cohorts to develop and validate a composite mutational signature of ERCC2 deficiency and cisplatin sensitivity. We identified a novel synthetic lethal relationship between tumor NER deficiency and sensitivity to irofulven. Irofulven specifically targets cells with inactivation of the transcription-coupled NER (TC-NER) pathway and leads to robust responses in vitro and in vivo, including in models with acquired cisplatin resistance, while having minimal effect on cells with intact NER. We also found that a composite mutational signature of ERCC2 deficiency was strongly associated with cisplatin response in patients and was also associated with cisplatin and irofulven sensitivity in preclinical models. Tumor NER deficiency confers sensitivity to irofulven, a previously abandoned anticancer agent, with minimal activity in NER-proficient cells. A composite mutational signature of NER deficiency may be useful in identifying patients likely to respond to NER-targeting agents, including cisplatin and irofulven.