Oncotarget

Research Papers:

Combinatorial drug screening of mammary cells with induced mesenchymal transformation to identify drug combinations for triple-negative breast cancer

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Oncotarget. 2019; 10:4822-4839. https://doi.org/10.18632/oncotarget.27104

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Sierra A. Colavito _, James T. Platt, Matthew A. Held, Zongzhi Liu, Ryan Sokup and David F. Stern

Abstract

Sierra A. Colavito1, James T. Platt2, Matthew A. Held3, Zongzhi Liu2, Ryan Sokup1 and David F. Stern4,5

1 Department of Biology, University of Wisconsin-La Crosse, La Crosse, WI, USA

2 Department of Internal Medicine and Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA

3 Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, USA

4 Department of Pathology, Yale School of Medicine, New Haven, CT, USA

5 Yale Cancer Center, New Haven, CT, USA

Correspondence to:

Sierra A. Colavito,email: scolavito@uwlax.edu

Keywords: epithelial-mesenchymal transition; triple-negative breast cancer; targeted drug combination screen; claudin-low breast cancer; CHK1

Received: June 25, 2019     Accepted: July 05, 2019     Published: August 06, 2019

ABSTRACT

Mesenchymal stem-like (MSL) breast cancers are enriched for cells with tumor reconstituting and mesenchymal characteristics. These cancers are often triple-negative and have a poor prognosis. Few effective targeted treatment options exist for patients with these cancers, and even when targeted therapies exist, resistance often arises and tumors recur, due in part to drug-tolerant persisting tumor cells with self-renewal capability. Effective treatment strategies will combine agents that target the bulk-tumor and reconstituting cells. In order to identify such a combination therapy, we conducted an inhibitor screen using 40 targeted agents at three different doses in all pairwise combinations. Checkpoint Kinase 1 (CHK1) inhibitors were identified as potent inhibitors of MSL breast cancers. When combined with a pro-apoptotic agent/B Cell Lymphoma 2 (BCL2) inhibitor, the effectiveness of the combination regimen was super-additive compared to either treatment alone and was selective for MSL cancers. Treatment of MSL breast cancer cells results in DNA damage, cell-cycle defects characterized by a prolonged S-phase, increased apoptosis and decreased colony forming abilities compared to untreated cells. These data suggest that a combination of a CHK1 and BCL2 inhibitor could be an effective treatment for patients with MSL breast cancer. Several other effective drug combinations were also identified.



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