CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer.
CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer.
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DOI：
10.1038/s41467-023-35880-y
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发表时间：
2023-01-17
影响因子：
16.6
通讯作者：
Jia, Li
中科院分区：
文献类型：
--
作者：
Tsujino, Takuya;Takai, Tomoaki;Hinohara, Kunihiko;Gui, Fu;Tsutsumi, Takeshi;Bai, Xiao;Miao, Chenkui;Feng, Chao;Gui, Bin;Sztupinszki, Zsofia;Simoneau, Antoine;Xie, Ning;Fazli, Ladan;Dong, Xuesen;Azuma, Haruhito;Choudhury, Atish D. D.;Mouw, Kent W. W.;Szallasi, Zoltan;Zou, Lee;Kibel, Adam S. S.;Jia, Li
携带 BRCA1/2 突变的前列腺癌通常对 PARP 抑制剂异常敏感。然而，其他 DNA 损伤反应基因的基因组改变并不能一致地预测 PARP 抑制的临床反应。在这里，我们在 BRCA1/2 熟练的前列腺癌细胞中进行全基因组 CRISPR-Cas9 敲除筛选，并鉴定了以前未知的基因，这些基因的缺失对 PARP 抑制剂反应具有深远的影响。具体来说，在前列腺癌中经常观察到的 MMS22L 缺失（高达 14%），通过破坏同源重组修复所需的 RAD51 负载，使细胞对 PARP 抑制剂过敏，尽管这种反应依赖于 TP53。出乎意料的是，CHEK2 的缺失通过增加 BRCA2（CHEK2-TP53-E2F7 介导的转录抑制的靶标）的表达而赋予对 PARP 抑制的抵抗性而不是敏感性。 PARP 和 ATR 联合抑制可克服因 CHEK2 缺失而引起的 PARP 抑制剂耐药性。我们的研究结果可能为 PARP 抑制剂在 BRCA1/2 缺陷肿瘤之外的使用提供信息，并支持重新评估前列腺癌中 PARP 抑制的当前生物标志物。识别可能对 PARP 抑制剂反应良好的前列腺癌患者对于他们在临床上取得成功非常重要。在这里，作者使用全基因组 CRISPR-Cas9 敲除筛选，将 MMS22L 确定为 BRCA1/2 熟练前列腺癌中 PARP 抑制敏感性的生物标志物。
Prostate cancer harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibition. Here, we perform genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient prostate cancer cells and identify previously unknown genes whose loss has a profound impact on PARP inhibitor response. Specifically, MMS22L deletion, frequently observed (up to 14%) in prostate cancer, renders cells hypersensitive to PARP inhibitors by disrupting RAD51 loading required for homologous recombination repair, although this response is TP53-dependent. Unexpectedly, loss of CHEK2 confers resistance rather than sensitivity to PARP inhibition through increased expression of BRCA2, a target of CHEK2-TP53-E2F7-mediated transcriptional repression. Combined PARP and ATR inhibition overcomes PARP inhibitor resistance caused by CHEK2 loss. Our findings may inform the use of PARP inhibitors beyond BRCA1/2-deficient tumors and support reevaluation of current biomarkers for PARP inhibition in prostate cancer. Identifying prostate cancer patients who may respond well to PARP inhibitors is important for their success in the clinic. Here, using a genome-wide CRISPR-Cas9 knockout screen, the authors identify MMS22L as a biomarker for sensitivity to PARP inhibition in BRCA1/2-proficient prostate cancer.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
--
作者：
Brookman-Amissah, Nicola;Nariculam, Joseph;Feneley, Mark R.
通讯作者：
Feneley, Mark R.
影响因子：
4.4
作者：
Dayebgadoh, Gerald;Sardiu, Mihaela E.;Washburn, Michael P.
通讯作者：
Washburn, Michael P.
具有转移性cast割前列腺癌的男性的鲁卡巴里（Rucaparib）具有BRCA1或BRCA2基因改变。
DOI：
10.1200/jco.20.01035
发表时间：
2020-11-10
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Abida W;Patnaik A;Campbell D;Shapiro J;Bryce AH;McDermott R;Sautois B;Vogelzang NJ;Bambury RM;Voog E;Zhang J;Piulats JM;Ryan CJ;Merseburger AS;Daugaard G;Heidenreich A;Fizazi K;Higano CS;Krieger LE;Sternberg CN;Watkins SP;Despain D;Simmons AD;Loehr A;Dowson M;Golsorkhi T;Chowdhury S;TRITON2 investigators
通讯作者：
TRITON2 investigators
影响因子：
82.9
作者：
Davies H;Glodzik D;Morganella S;Yates LR;Staaf J;Zou X;Ramakrishna M;Martin S;Boyault S;Sieuwerts AM;Simpson PT;King TA;Raine K;Eyfjord JE;Kong G;Borg Å;Birney E;Stunnenberg HG;van de Vijver MJ;Børresen-Dale AL;Martens JW;Span PN;Lakhani SR;Vincent-Salomon A;Sotiriou C;Tutt A;Thompson AM;Van Laere S;Richardson AL;Viari A;Campbell PJ;Stratton MR;Nik-Zainal S
通讯作者：
Nik-Zainal S