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A Combinatorial CRISPR-Cas9 Screen Identifies Ifenprodil as an Adȷunct to Sorafenib for Liver Cancer Treatment
Cancer Research ( IF 12.5 ) Pub Date : 2021-12-15 , DOI: 10.1158/0008-5472.can-21-1017
Feng Xu 1 , Man Tong 2, 3 , Cindy S W Tong 1 , Becky K C Chan 1 , Hoi Yee Chu 1 , Tin Lok Wong 2 , John H C Fong 1 , Maggie S H Cheung 1 , Kylie Hin-Man Mak 1 , Lakhansing Pardeshi 4, 5 , Yuanhua Huang 2, 6 , Koon Ho Wong 4, 7, 8 , Gigi C G Choi 1 , Stephanie Ma 2, 9 , Alan S L Wong 1, 10
Affiliation  

Systematic testing of existing drugs and their combinations is an attractive strategy to exploit approved drugs for repurposing and identifying the best actionable treatment options. To expedite the search among many possible drug combinations, we designed a combinatorial CRISPR–Cas9 screen to inhibit druggable targets. Coblockade of the N-methyl-d-aspartate receptor (NMDAR) with targets of first-line kinase inhibitors reduced hepatocellular carcinoma (HCC) cell growth. Clinically, HCC patients with low NMDAR1 expression showed better survival. The clinically approved NMDAR antagonist ifenprodil synergized with sorafenib to induce the unfolded protein response, trigger cell-cycle arrest, downregulate genes associated with WNT signaling and stemness, and reduce self-renewal ability of HCC cells. In multiple HCC patient-derived organoids and human tumor xenograft models, the drug combination, but neither single drug alone, markedly reduced tumor-initiating cancer cell frequency. Because ifenprodil has an established safety history for its use as a vasodilator in humans, our findings support the repurposing of this drug as an adjunct for HCC treatment to improve clinical outcome and reduce tumor recurrence. These results also validate an approach for readily discovering actionable combinations for cancer therapy. Significance: Combinatorial CRISPR–Cas9 screening identifies actionable targets for HCC therapy, uncovering the potential of combining the clinically approved drugs ifenprodil and sorafenib as a new effective treatment regimen.

中文翻译:

组合 CRISPR-Cas9 筛选确定艾芬地尔是索拉非尼治疗肝癌的一种辅助药物

对现有药物及其组合进行系统测试是一种有吸引力的策略,可以利用已批准的药物重新利用和确定最佳可行的治疗方案。为了加快在许多可能的药物组合中的搜索,我们设计了一种组合 CRISPR-Cas9 筛选来抑制可药用靶标。N-甲基-d-天冬氨酸受体 (NMDAR) 与一线激酶抑制剂靶点的共阻断减少了肝细胞癌 (HCC) 细胞的生长。临床上,低 NMDAR1 表达的 HCC 患者表现出更好的生存率。临床批准的 NMDAR 拮抗剂艾芬地尔与索拉非尼协同诱导未折叠蛋白反应,触发细胞周期停滞,下调与 WNT 信号和干性相关的基因,并降低 HCC 细胞的自我更新能力。在多个 HCC 患者衍生的类器官和人类肿瘤异种移植模型中,药物组合,但不是单独的单一药物,显着降低了肿瘤起始癌细胞的频率。由于艾芬地尔在人类中用作血管扩张剂具有既定的安全历史,我们的研究结果支持将该药物重新用作 HCC 治疗的辅助剂,以改善临床结果并减少肿瘤复发。这些结果还验证了一种易于发现癌症治疗可行组合的方法。意义:组合 CRISPR-Cas9 筛选确定了 HCC 治疗的可行靶点,揭示了将临床批准的药物艾芬地尔和索拉非尼联合作为一种新的有效治疗方案的潜力。显着降低肿瘤起始癌细胞的频率。由于艾芬地尔在人类中用作血管扩张剂具有既定的安全历史,我们的研究结果支持将该药物重新用作 HCC 治疗的辅助剂,以改善临床结果并减少肿瘤复发。这些结果还验证了一种易于发现癌症治疗可行组合的方法。意义:组合 CRISPR-Cas9 筛选确定了 HCC 治疗的可行靶点,揭示了将临床批准的药物艾芬地尔和索拉非尼联合作为一种新的有效治疗方案的潜力。显着降低肿瘤起始癌细胞的频率。由于艾芬地尔在人类中用作血管扩张剂具有既定的安全历史,我们的研究结果支持将该药物重新用作 HCC 治疗的辅助剂,以改善临床结果并减少肿瘤复发。这些结果还验证了一种易于发现癌症治疗可行组合的方法。意义:组合 CRISPR-Cas9 筛选确定了 HCC 治疗的可行靶点,揭示了将临床批准的药物艾芬地尔和索拉非尼联合作为一种新的有效治疗方案的潜力。我们的研究结果支持将该药物重新用作 HCC 治疗的辅助药物,以改善临床结果并减少肿瘤复发。这些结果还验证了一种易于发现癌症治疗可行组合的方法。意义:组合 CRISPR-Cas9 筛选确定了 HCC 治疗的可行靶点,揭示了将临床批准的药物艾芬地尔和索拉非尼联合作为一种新的有效治疗方案的潜力。我们的研究结果支持将该药物重新用作 HCC 治疗的辅助药物,以改善临床结果并减少肿瘤复发。这些结果还验证了一种易于发现癌症治疗可行组合的方法。意义:组合 CRISPR-Cas9 筛选确定了 HCC 治疗的可行靶点,揭示了将临床批准的药物艾芬地尔和索拉非尼联合作为一种新的有效治疗方案的潜力。
更新日期:2021-12-15
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