Cross-species genomic and functional analyses identify a combination therapy using a CHK1 inhibitor and a ribonucleotide reductase inhibitor to treat triple-negative breast cancer.
Cross-species genomic and functional analyses identify a combination therapy using a CHK1 inhibitor and a ribonucleotide reductase inhibitor to treat triple-negative breast cancer.
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DOI：
10.1186/bcr3230
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发表时间：
2012-07-19
期刊：
影响因子：
--
通讯作者：
Green JE
中科院分区：
文献类型：
--
作者：
Bennett CN;Tomlinson CC;Michalowski AM;Chu IM;Luger D;Mittereder LR;Aprelikova O;Shou J;Piwinica-Worms H;Caplen NJ;Hollingshead MG;Green JE
三阴性乳腺癌(TNBC)是乳腺癌的一种侵袭性亚型，约占所有人类乳腺癌(BRCA)患者的15%。目前，还没有针对这一亚型BRCA的靶向治疗方法，预后仍然很差。我们的实验室以前已经发现了一个人类TNBC特有的增殖/DNA修复/细胞周期基因签名(标签签名)。我们假设，针对标签基因签名中的失调生物网络将导致对TNBC的改进的联合疗法的识别。跨物种基因组分析被用来鉴定表达标签签名的人乳腺癌细胞系。通过siRNA下调标签签名中上调的基因，确定了几个对TNBC细胞生长至关重要的基因。对其中两个基因的小分子抑制剂进行了单独和联合分析，以了解它们在体外对细胞增殖、细胞周期、细胞凋亡和体内肿瘤生长的影响。用Chou-Talalay法分析两药的协同作用。使用定制的siRNA筛选来识别标签签名内对TNBC细胞生长至关重要的靶点。核糖核苷酸还原酶1和2(RRM1和2)和检查点激酶1(CHK1)被发现是TNBC细胞生存的关键靶点。联合治疗，通过抑制CHK1来减弱细胞周期检查点控制，同时用吉西他滨诱导DNA损伤，在体外和在TNBC异种移植模型中提高了治疗效果。这种联合疗法可能对TNBC患者具有翻译价值，并改善这种侵袭性乳腺癌的治疗反应。
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is diagnosed in approximately 15% of all human breast cancer (BrCa) patients. Currently, no targeted therapies exist for this subtype of BrCa and prognosis remains poor. Our laboratory has previously identified a proliferation/DNA repair/cell cycle gene signature (Tag signature) that is characteristic of human TNBC. We hypothesize that targeting the dysregulated biological networks in the Tag gene signature will lead to the identification of improved combination therapies for TNBC. Cross-species genomic analysis was used to identify human breast cancer cell lines that express the Tag signature. Knock-down of the up-regulated genes in the Tag signature by siRNA identified several genes that are critical for TNBC cell growth. Small molecule inhibitors to two of these genes were analyzed, alone and in combination, for their effects on cell proliferation, cell cycle, and apoptosis in vitro and tumor growth in vivo. Synergy between the two drugs was analyzed by the Chou-Talalay method. A custom siRNA screen was used to identify targets within the Tag signature that are critical for growth of TNBC cells. Ribonucleotide reductase 1 and 2 (RRM1 and 2) and checkpoint kinase 1 (CHK1) were found to be critical targets for TNBC cell survival. Combination therapy, to simultaneously attenuate cell cycle checkpoint control through inhibition of CHK1 while inducing DNA damage with gemcitabine, improved therapeutic efficacy in vitro and in xenograft models of TNBC. This combination therapy may have translational value for patients with TNBC and improve therapeutic response for this aggressive form of breast cancer.
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影响因子：
3
作者：
Fracasso, Paula M.;Williams, Kerry J.;Chen, Ronald C.;Picus, Joel;Ma, Cynthia X.;Ellis, Matthew J.;Tan, Benjamin R.;Pluard, Timothy J.;Adkins, Douglas R.;Naughton, Michael J.;Rader, Janet S.;Arquette, Matthew A.;Fleshman, James W.;Creekmore, Allison N.;Goodner, Sherry A.;Wright, Lisa P.;Guo, Zhanfang;Ryan, Christine E.;Tao, Yu;Soares, Eliane M.;Cai, Shi-rong;Lin, Li;Dancey, Janet;Rudek, Michelle A.;McLeod, Howard L.;Piwnica-Worms, Helen
通讯作者：
Piwnica-Worms, Helen
DOI：
10.1097/pas.0b013e31817f9790
发表时间：
2009-02
期刊：
The American journal of surgical pathology
影响因子：
--
作者：
Subhawong AP;Subhawong T;Nassar H;Kouprina N;Begum S;Vang R;Westra WH;Argani P
通讯作者：
Argani P
影响因子：
12.3
作者：
Herschkowitz JI;Simin K;Weigman VJ;Mikaelian I;Usary J;Hu Z;Rasmussen KE;Jones LP;Assefnia S;Chandrasekharan S;Backlund MG;Yin Y;Khramtsov AI;Bastein R;Quackenbush J;Glazer RI;Brown PH;Green JE;Kopelovich L;Furth PA;Palazzo JP;Olopade OI;Bernard PS;Churchill GA;Van Dyke T;Perou CM
通讯作者：
Perou CM
影响因子：
11.2
作者：
Deeb, Kristin K.;Michalowska, Aleksandra M.;Green, Jeffrey E.
通讯作者：
Green, Jeffrey E.
影响因子：
4.8
作者：
Graves, PR;Yu, LJ;Piwnica-Worms, H
通讯作者：
Piwnica-Worms, H