Oncotarget

Priority Research Papers:

Integrated in vivo genetic and pharmacologic screening identifies co-inhibition of EGRF and ROCK as a potential treatment regimen for triple-negative breast cancer

Sedef Iskit, Cor Lieftink, Pasi Halonen, Aida Shahrabi, Patricia A. Possik, Roderick L. Beijersbergen and Daniel S. Peeper _

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Oncotarget. 2016; 7:42859-42872. https://doi.org/10.18632/oncotarget.10230

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Abstract

Sedef Iskit1, Cor Lieftink2, Pasi Halonen3, Aida Shahrabi1, Patricia A. Possik4, Roderick L. Beijersbergen2 and Daniel S. Peeper1

1 Department of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan, Amsterdam, The Netherlands

2 Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan, Amsterdam, The Netherlands

3 Drug Discovery Research and Screening Services, BioFocus, Darwinweg, Leiden

4 Brazilian National Cancer Institute, Rio de Janeiro, Brazil

Correspondence to:

Daniel S. Peeper, email:

Keywords: in vivo screen, targeted therapy, TNBC, EGFR, ROCK

Received: January 13, 2016 Accepted: June 09, 2016 Published: June 22, 2016

Abstract

Breast cancer is the second most common cause of cancer-related deaths worldwide among women. Despite several therapeutic options, 15% of breast cancer patients succumb to the disease owing to tumor relapse and acquired therapy resistance. Particularly in triple-negative breast cancer (TNBC), developing effective treatments remains challenging owing to the lack of a common vulnerability that can be exploited by targeted approaches. We have previously shown that tumor cells have different requirements for growth in vivo than in vitro. Therefore, to discover novel drug targets for TNBC, we performed parallel in vivo and in vitro genetic shRNA dropout screens. We identified several potential drug targets that were required for tumor growth in vivo to a greater extent than in vitro. By combining pharmacologic inhibitors acting on a subset of these candidates, we identified a synergistic interaction between EGFR and ROCK inhibitors. This combination effectively reduced TNBC cell growth by inducing cell cycle arrest. These results illustrate the power of in vivo genetic screens and warrant further validation of EGFR and ROCK as combined pharmacologic targets for breast cancer.


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