Identifying CDC7 as a synergistic target of chemotherapy in resistant small-cell lung cancer via CRISPR/Cas9 screening.
Identifying CDC7 as a synergistic target of chemotherapy in resistant small-cell lung cancer via CRISPR/Cas9 screening.
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DOI：
10.1038/s41420-023-01315-2
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发表时间：
2023-02-02
影响因子：
7
通讯作者：
Guo, Linlang
中科院分区：
文献类型：
--
作者：
Deng, Ling;Yang, Li;Zhu, Shuhan;Li, Man;Wang, Yu;Cao, Xiaolong;Wang, Qiongyao;Guo, Linlang
目前对耐药小细胞肺癌（SCLC）患者缺乏有效的治疗方法，导致预后不良。我们使用全基因组CRISPR/Cas9筛选检查了化学抗性SCLC细胞系，并将丝氨酸/苏氨酸激酶细胞分裂周期7（CDC 7）鉴定为潜在的协同靶标。在化疗耐药的SCLC细胞中沉默CDC 7降低了IC 50并提高了化疗的疗效。基于最高单药模型，CDC 7抑制剂XL 413与顺铂和依托泊苷在化疗耐药的SCLC细胞中具有协同作用，但在化疗敏感的SCLC细胞中没有这种作用; XL 413和化疗的组合显著抑制细胞生长。Western blot和流式细胞术显示，联合处理增加了细胞凋亡，而XL 413单独处理对细胞凋亡的影响不大。细胞周期和cyclin蛋白水平的分析表明，XL 413和化疗的组合诱导化疗耐药的SCLC细胞的G1/S期阻滞和DNA损伤。使用患者来源的异种移植物进行的异种移植肿瘤和组织培养药物反应测定表明，XL 413改善了体内化疗和SCLC组织的疗效。这些结果表明，XL 413与化疗对化疗耐药的SCLC发挥协同作用。
There is currently a lack of efficacious treatments for patients with chemo-resistant small-cell lung cancer (SCLC), leading to poor prognoses. We examined a chemo-resistant SCLC cell line using genome-wide CRISPR/Cas9 screening and identified serine/threonine kinase cell division cycle 7 (CDC7) as a potential synergistic target. Silencing CDC7 in chemo-resistant SCLC cells decreased the IC50 and improved the efficacy of chemotherapy. Based on the highest single agent model, the CDC7 inhibitor XL413 had a synergistic effect with both cisplatin and etoposide in chemo-resistant SCLC cells, but had no such effect in chemo-sensitive SCLC cells; the combination of XL413 and chemotherapy significantly inhibited cell growth. Western blot and flow cytometry showed that the combined treatments increased apoptosis, whereas XL413 alone had little effect on apoptosis. An analysis of cell cycle and cyclin protein levels indicated that the combination of XL413 and chemotherapy-induced G1/S phase arrest and DNA damage in chemo-resistant SCLC cells. Xenografted tumor and histoculture drug response assays using patient-derived xenografts showed that XL413 improved the efficacy of chemotherapy in vivo and with SCLC tissues. These results suggest that XL413 exerts a synergistic effect with chemotherapy on chemo-resistant SCLC.
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小细胞肺癌患者的生存变化以及不同性别、社会经济地位和年龄之间的差异
影响因子：
4.6
作者：
Wang S;Tang J;Sun T;Zheng X;Li J;Sun H;Zhou X;Zhou C;Zhang H;Cheng Z;Ma H;Sun H
通讯作者：
Sun H
影响因子：
11.2
作者：
Quintanal-Villalonga A;Taniguchi H;Hao Y;Chow A;Zhan YA;Chavan SS;Uddin F;Allaj V;Manoj P;Shah NS;Chan JM;Offin M;Ciampricotti M;Ray-Kirton J;Egger J;Bhanot U;Linkov I;Asher M;Roehrl MH;Qiu J;de Stanchina E;Hollmann TJ;Koche RP;Sen T;Poirier JT;Rudin CM
通讯作者：
Rudin CM
DOI：
10.1038/s41572-020-00235-0
发表时间：
2021-01-14
期刊：
Nature reviews. Disease primers
影响因子：
--
作者：
Rudin CM;Brambilla E;Faivre-Finn C;Sage J
通讯作者：
Sage J
影响因子：
2.9
作者：
Zhou, Xiaofei;Ouerdani, Aziz;Diderichsen, Paul Matthias;Gupta, Neeraj
通讯作者：
Gupta, Neeraj
影响因子：
10.5
作者：
Huang YH;Klingbeil O;He XY;Wu XS;Arun G;Lu B;Somerville TDD;Milazzo JP;Wilkinson JE;Demerdash OE;Spector DL;Egeblad M;Shi J;Vakoc CR
通讯作者：
Vakoc CR