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Targeting Chk1 in p53-deficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models
Cynthia X. Ma, … , Matthew J. Ellis, Helen Piwnica-Worms
Cynthia X. Ma, … , Matthew J. Ellis, Helen Piwnica-Worms
Published March 26, 2012
Citation Information: J Clin Invest. 2012;122(4):1541-1552. https://doi.org/10.1172/JCI58765.
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Research Article Article has an altmetric score of 11

Targeting Chk1 in p53-deficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models

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Abstract

Patients with triple-negative breast cancer (TNBC) — defined by lack of estrogen receptor and progesterone receptor expression as well as lack of human epidermal growth factor receptor 2 (HER2) amplification — have a poor prognosis. There is a need for targeted therapies to treat this condition. TNBCs frequently harbor mutations in TP53, resulting in loss of the G1 checkpoint and reliance on checkpoint kinase 1 (Chk1) to arrest cells in response to DNA damage. Previous studies have shown that inhibition of Chk1 in a p53-deficient background in response to DNA damage. We therefore tested whether inhibition of Chk1 could potentiate the cytotoxicity of the DNA damaging agent irinotecan in TNBC using xenotransplant tumor models. Tumor specimens from patients with TNBC were engrafted into humanized mammary fat pads of immunodeficient mice to create 3 independent human-in-mouse TNBC lines: 1 WT (WU-BC3) and 2 mutant for TP53 (WU-BC4 and WU-BC5). These lines were tested for their response to irinotecan and a Chk1 inhibitor (either UCN-01 or AZD7762), either as single agents or in combination. The combination therapy induced checkpoint bypass and apoptosis in WU-BC4 and WU-BC5, but not WU-BC3, tumors. Moreover, combination therapy inhibited tumor growth and prolonged survival of mice bearing the WU-BC4 line, but not the WU-BC3 line. In addition, knockdown of p53 sensitized WU-BC3 tumors to the combination therapy. These results demonstrate that p53 is a major determinant of how TNBCs respond to therapies that combine DNA damage with Chk1 inhibition.

Authors

Cynthia X. Ma, Shirong Cai, Shunqiang Li, Christine E. Ryan, Zhanfang Guo, W. Timothy Schaiff, Li Lin, Jeremy Hoog, Reece J. Goiffon, Aleix Prat, Rebecca L. Aft, Matthew J. Ellis, Helen Piwnica-Worms

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Figure 4

Chk1 inhibitors enhance DNA damage and abrogate cell-cycle arrest induced by irinotecan selectively in p53 mutant tumors.

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Chk1 inhibitors enhance DNA damage and abrogate cell-cycle arrest induce...
Mice harboring WU-BC3 and WU-BC4 TNBC were treated as indicated, and tumors were costained for phosphohistone H3 (pH3, red) and γH2AX (green). Representative IF images are shown in A and B, and quantitation ± 95% CIs are shown in C–E. Statistics were obtained by the Wilson score method in SPSS 20. **P < 0.01; ***P < 0.001. Original magnification, ×400. (F) Mice harboring WU-BC3 or WU-BC4 tumors were treated as indicated; tumors were lysed and analyzed by Western blotting with antibodies specific for S6 ribosomal protein, phosphorylated S6 ribosomal protein (pS6), and actin as a loading control. The ratio of phosphorylated S6 to total S6 protein was determined for each sample. Blots were developed using ECL detection reagent (GE Healthcare), and proteins were quantitated using ImageJ (53). Mean ratios are shown with 95% CIs. *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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