Oncotarget

Research Papers:

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

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

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

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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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