CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer.
CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer.
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DOI：
10.3390/cancers13205056
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发表时间：
2021-10-09
期刊：
影响因子：
5.2
通讯作者：
Landen CN
中科院分区：
文献类型：
--
作者：
Cornelison R;Biswas K;Llaneza DC;Harris AR;Sosale NG;Lazzara MJ;Landen CN
CX-5461是一种RNA聚合酶I抑制剂，正在对晚期血液癌和实体瘤进行临床试验。在实验上，这种药物已经被证明通过ATM和ATR激酶诱导不依赖于p53的DNA损伤反应，并且对耐药肿瘤具有特殊的活性。目前的研究首次表明，CX-5461处理卵巢癌细胞可以诱导胞浆DNA的释放，刺激cGAS-STING信号，导致体内癌细胞和异种移植瘤产生I型干扰素。由于cGAS-STING通路是针对癌细胞的免疫反应的关键介质，这一新的发现可能导致将RNA Pol I抑制剂与检查点抑制结合使用。上皮性卵巢癌(EOC)是妇科恶性肿瘤中死亡率最高的，总存活率为30%。最近的研究表明，靶向RNA聚合酶I(POL I)的小分子抑制剂可能是一种可行的抗上皮性卵巢癌的治疗方法，即使存在化疗耐药。CX-5461是目前正在研究的最有前景的POL I抑制剂之一，以往的报道表明，CX-5461处理后通过ATM/ATR激酶诱导DNA损伤反应(DDR)。对CX-5461下游效应的调查使我们发现了一种以前未报道的表型。用CX-5461处理后，胞质DNA快速积聚。这种积累导致‘干扰素基因刺激物’(STING)在同一时间框架内转录上调，IRF3的磷酸化，以及在体外和体内I型干扰素反应的激活。这种激活是由环状GMP-AMP合成酶(CGAS)介导并依赖的。在这里，我们发现CX-5461导致胞浆dsDNA的积聚，从而激活cGAS-STING-TBK1-IRF3天然免疫途径，从而诱导I型干扰素。CX-5461治疗介导的免疫激活可能是一个值得开发的强大作用机制，导致新的药物组合有机会提高免疫治疗效果，可能具有一些癌症特异性限制有害毒性。
CX-5461 is an RNA polymerase I inhibitor that is in clinical trials for both advanced hematological cancers and solid tumors. Experimentally, this drug has been shown to induce a p53-independent DNA damage response through ATM and ATR kinase, and has particular activity against chemoresistant tumors. The current study shows for the first time that CX-5461 treatment in ovarian cancer cells induces the release of cytoplasmic DNA that stimulates cGAS–STING signaling, leading to the production of IFN type I in both cancer cells and xenografts in vivo. Because the cGAS–STING pathway is a key mediator of the immune response against cancer cells, this novel finding may lead to utilization of RNA Pol I inhibitors in combination with checkpoint inhibition. Epithelial ovarian cancer (EOC) is the deadliest of the gynecologic malignancies, with an overall survival rate of <30%. Recent research has suggested that targeting RNA polymerase I (POL I) with small-molecule inhibitors may be a viable therapeutic approach to combating EOC, even when chemoresistance is present. CX-5461 is one of the most promising POL I inhibitors currently being investigated, and previous reports have shown that CX-5461 treatment induces DNA damage response (DDR) through ATM/ATR kinase. Investigation into downstream effects of CX-5461 led us to uncovering a previously unreported phenotype. Treatment with CX-5461 induces a rapid accumulation of cytosolic DNA. This accumulation leads to transcriptional upregulation of ‘STimulator of Interferon Genes’ (STING) in the same time frame, phosphorylation of IRF3, and activation of type I interferon response both in vitro and in vivo. This activation is mediated and dependent on cyclic GMP–AMP synthase (cGAS). Here, we show THAT CX-5461 leads to an accumulation of cytosolic dsDNA and thereby activates the cGAS–STING–TBK1–IRF3 innate immune pathway, which induces type I IFN. CX-5461 treatment-mediated immune activation may be a powerful mechanism of action to exploit, leading to novel drug combinations with a chance of increasing immunotherapy efficacy, possibly with some cancer specificity limiting deleterious toxicities.
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影响因子：
64.8
作者：
Dou Z;Ghosh K;Vizioli MG;Zhu J;Sen P;Wangensteen KJ;Simithy J;Lan Y;Lin Y;Zhou Z;Capell BC;Xu C;Xu M;Kieckhaefer JE;Jiang T;Shoshkes-Carmel M;Tanim KMAA;Barber GN;Seykora JT;Millar SE;Kaestner KH;Garcia BA;Adams PD;Berger SL
通讯作者：
Berger SL
影响因子：
3.2
作者：
Sokolowska O;Nowis D
通讯作者：
Nowis D
DOI：
10.1038/nrc4019
发表时间：
2015-11
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Bowtell DD;Böhm S;Ahmed AA;Aspuria PJ;Bast RC Jr;Beral V;Berek JS;Birrer MJ;Blagden S;Bookman MA;Brenton JD;Chiappinelli KB;Martins FC;Coukos G;Drapkin R;Edmondson R;Fotopoulou C;Gabra H;Galon J;Gourley C;Heong V;Huntsman DG;Iwanicki M;Karlan BY;Kaye A;Lengyel E;Levine DA;Lu KH;McNeish IA;Menon U;Narod SA;Nelson BH;Nephew KP;Pharoah P;Powell DJ Jr;Ramos P;Romero IL;Scott CL;Sood AK;Stronach EA;Balkwill FR
通讯作者：
Balkwill FR
影响因子：
5.3
作者：
Song, Xuan;Ma, Fulin;Herrupu, OKarl
通讯作者：
Herrupu, OKarl
影响因子：
5.2
作者：
de Queiroz, Nina Mari Gual Pimenta;Xia, Tianli;Barber, Glen N.
通讯作者：
Barber, Glen N.