Targeting Replicative Stress and DNA Repair by Combining PARP and Wee1 Kinase Inhibitors Is Synergistic in Triple Negative Breast Cancers with Cyclin E or BRCA1 Alteration.
Targeting Replicative Stress and DNA Repair by Combining PARP and Wee1 Kinase Inhibitors Is Synergistic in Triple Negative Breast Cancers with Cyclin E or BRCA1 Alteration.
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DOI：
10.3390/cancers13071656
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发表时间：
2021-04-01
期刊：
影响因子：
5.2
通讯作者：
Keyomarsi K
中科院分区：
文献类型：
--
作者：
Chen X;Yang D;Carey JPW;Karakas C;Albarracin C;Sahin AA;Arun BK;Guray Durak M;Li M;Kohansal M;Bui TN;Ha MJ;Hunt KK;Keyomarsi K
三阴性乳腺癌(TNBC)是浸润性乳腺癌的一种亚型，与其他类型的乳腺癌相比，其侵袭性表型降低了生存率，部分原因是缺乏生物标记物驱动的靶向治疗。在这里，我们表明，肿瘤细胞周期蛋白E表达水平高的乳腺癌患者BRCA1/2改变的发生率较高，临床结果最差。体外和体内研究表明，在BRCA1突变或高水平周期蛋白E的TNBC细胞中，多聚ADP-核糖聚合酶(PARP)和Wee1激酶抑制剂联合治疗会导致细胞协同死亡，原因是诱导复制应激和DNA修复下调。这些研究表明，通过预先选择肿瘤具有高周期蛋白E水平或BRCA1基因突变的患者，只有那些具有最高复制应激特性的患者才会接受联合治疗，并可能导致两种药物的协同活性。由于缺乏特定的靶点，识别生物标记物驱动的靶向治疗三阴性乳腺癌(TNBC)患者仍然是一个重大的临床挑战。在这里，我们证明了细胞周期蛋白E是G1向S转变的主要调节因子，在肿瘤细胞中被解除调控，并与DNA修复基因(如BRCA1/2)的突变有关。周期蛋白E水平高的乳腺癌不仅BRCA1/2突变的发生率较高，而且与最差的预后相关。利用几种体外和体内模型系统，我们发现具有BRCA1/2突变或周期蛋白E过度表达的TNBCs对WE1激酶抑制剂AZD-1775和PARP抑制剂MK-4837的生长抑制作用非常敏感。这两种药物联合作用可诱导复制应激、DNA修复下调和胞质分裂失败，从而导致细胞凋亡增加，从而产生协同杀伤作用。这些发现突出了使用Cyclin E和BRCA突变作为生物标记物的潜在临床应用，以选择那些具有最高复制应激特性的患者，这些患者可能受益于Wee 1激酶和PARP抑制剂的联合治疗。
Triple-negative breast cancer (TNBC) is a subtype of invasive breast cancer with an aggressive phenotype that has decreased survival compared with other types of breast cancers, due in part to the lack of biomarker driven targeted therapies. Here, we show that breast cancer patients whose tumors show high levels of cyclin E expression have a higher prevalence of BRCA1/2 alterations and have the worst clinical outcomes. In vitro and in vivo studies revealed that combination therapies with poly (ADP-ribose) polymerase (PARP) and Wee1 kinase inhibitors in TNBC cells with either BRCA1 mutations or high levels of cyclin E results in synergistic cell death due to induction of replicative stress and downregulation of DNA repair. These studies suggest that by preselecting patients whose tumors have high cyclin E levels or harbor mutations in BRCA1, only those cases with the highest replicative stress properties will be subjected to combination treatment and likely result in synergistic activity of the two agents. The identification of biomarker-driven targeted therapies for patients with triple negative breast cancer (TNBC) remains a major clinical challenge, due to a lack of specific targets. Here, we show that cyclin E, a major regulator of G1 to S transition, is deregulated in TNBC and is associated with mutations in DNA repair genes (e.g., BRCA1/2). Breast cancers with high levels of cyclin E not only have a higher prevalence of BRCA1/2 mutations, but also are associated with the worst outcomes. Using several in vitro and in vivo model systems, we show that TNBCs that harbor either mutations in BRCA1/2 or overexpression of cyclin E are very sensitive to the growth inhibitory effects of AZD-1775 (Wee 1 kinase inhibitor) when used in combination with MK-4837 (PARP inhibitor). Combination treatment of TNBC cell lines with these two agents results in synergistic cell killing due to induction of replicative stress, downregulation of DNA repair and cytokinesis failure that results in increased apoptosis. These findings highlight the potential clinical application of using cyclin E and BRCA mutations as biomarkers to select only those patients with the highest replicative stress properties that may benefit from combination treatment with Wee 1 kinase and PARP inhibitors.
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影响因子：
16.8
作者：
Berti, Matteo;Chaudhuri, Arnab Ray;Thangavel, Saravanabhavan;Gomathinayagam, Shivasankari;Kenig, Sasa;Vujanovic, Marko;Odreman, Federico;Glatter, Timo;Graziano, Simona;Mendoza-Maldonado, Ramiro;Marino, Francesca;Lucic, Bojana;Biasin, Valentina;Gstaiger, Matthias;Aebersold, Ruedi;Sidorova, Julia M.;Monnat, Raymond J., Jr.;Lopes, Massimo;Vindigni, Alessandro
通讯作者：
Vindigni, Alessandro
影响因子：
29.4
作者：
Dreyer SB;Upstill-Goddard R;Paulus-Hock V;Paris C;Lampraki EM;Dray E;Serrels B;Caligiuri G;Rebus S;Plenker D;Galluzzo Z;Brunton H;Cunningham R;Tesson M;Nourse C;Bailey UM;Jones M;Moran-Jones K;Wright DW;Duthie F;Oien K;Evers L;McKay CJ;McGregor GA;Gulati A;Brough R;Bajrami I;Pettitt S;Dziubinski ML;Candido J;Balkwill F;Barry ST;Grützmann R;Rahib L;Glasgow Precision Oncology Laboratory,;Australian Pancreatic Cancer Genome Initiative;Johns A;Pajic M;Froeling FEM;Beer P;Musgrove EA;Petersen GM;Ashworth A;Frame MC;Crawford HC;Simeone DM;Lord C;Mukhopadhyay D;Pilarsky C;Tuveson DA;Cooke SL;Jamieson NB;Morton JP;Sansom OJ;Bailey PJ;Biankin AV;Chang DK
通讯作者：
Chang DK
影响因子：
28.2
作者：
Aarts, Marieke;Sharpe, Rachel;Turner, Nicholas C.
通讯作者：
Turner, Nicholas C.
影响因子：
8
作者：
Chow, J. P. H.;Poon, R. Y. C.
通讯作者：
Poon, R. Y. C.
影响因子：
4.7
作者：
Aziz, Diar;Etemadmoghadam, Dariush;Waring, Paul
通讯作者：
Waring, Paul