Checkpoint kinase 1 protein expression indicates sensitization to therapy by checkpoint kinase 1 inhibition in non-small cell lung cancer.
Checkpoint kinase 1 protein expression indicates sensitization to therapy by checkpoint kinase 1 inhibition in non-small cell lung cancer.
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DOI：
10.1016/j.jss.2013.12.016
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发表时间：
2014-03
影响因子：
2.2
通讯作者：
Reddy, Rishindra M.
中科院分区：
文献类型：
--
作者：
Grabauskiene, Svetlana;Bergeron, Edward J.;Chen, Guoan;Thomas, Dafydd G.;Giordano, Thomas J.;Beer, David G.;Morgan, Meredith A.;Reddy, Rishindra M.
When presenting with advanced stage disease, lung cancer patients have <5% 5-y survival. The overexpression of checkpoint kinase 1 (CHK1) is associated with poorer outcomes and may contribute to therapy resistance. Targeting CHK1 with small-molecule inhibitors in p53 mutant tumors might improve the effectiveness of chemotherapy and radiotherapy in non–small cell lung cancer (NSCLC). We evaluatedCHK1 messenger RNA and protein levels in multiple NSCLC cell lines. We assessed cell line sensitization to gemcitabine, pemetrexed, and radiotherapy by CHK1 inhibition with the small molecule AZD7762 using proliferation and clonogenic cell survival assays. We analyzed CHK1 signaling by Western blotting to confirm that AZD7762 inhibits CHK1. We selected two p53 mutant NSCLC cell lines with either high (H1299) or low (H1993) CHK1 levels for further analysis. We found that AZD7762 sensitized both cell lines to gemcitabine, pemetrexed, and radiotherapy. Chemosensitization levels were greater, however, for the higher CHK1 protein expressing cell line, H1299, when compared with H1993. Furthermore, analysis of the CHK1 signaling pathway showed that H1299 cells have an increased dependence on the CHK1 pathway in response to chemotherapy. There was no increased sensitization to radiation in H1299 versus H1993. CHK1 inhibition by AZD7762 preferentially sensitizes high CHK1 expressing cells, H1299, to anti-metabolite chemotherapy as compared with low CHK1 expressing H1993 cells. Thus, CHK1 inhibitors may improve the efficacy of standard lung cancer therapies, especially for those subgroups of tumors harboring higher expression levels of CHK1 protein.
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影响因子：
5.7
作者：
Parsels LA;Morgan MA;Tanska DM;Parsels JD;Palmer BD;Booth RJ;Denny WA;Canman CE;Kraker AJ;Lawrence TS;Maybaum J
通讯作者：
Maybaum J
影响因子：
6.4
作者：
Chen, Zehan;Xiao, Zhan;Zhang, Haiying
通讯作者：
Zhang, Haiying
影响因子：
5.2
作者：
Thompson, Ruth;Meuth, Mark;Danson, Sarah
通讯作者：
Danson, Sarah
DOI：
10.1158/1078-0432.ccr-09-3277
发表时间：
2010-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Mitchell JB;Choudhuri R;Fabre K;Sowers AL;Citrin D;Zabludoff SD;Cook JA
通讯作者：
Cook JA
影响因子：
3.7
作者：
Bryant CM;Albertus DL;Kim S;Chen G;Brambilla C;Guedj M;Arima C;Travis WD;Yatabe Y;Takahashi T;Brambilla E;Beer DG
通讯作者：
Beer DG