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Dasatinib attenuates overexpression of Src signaling induced by the combination treatment of veliparib plus carboplatin in triple-negative breast cancer

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Abstract

Purpose

Triple-negative breast cancer (TNBC) has a poor prognosis because of limited treatment options. The combination of a poly ADP ribose polymerase (PARP) inhibitor with a DNA-damaging agent has shown promise in treating TNBC; however, not all patients respond to this combination. The Src protein kinase modulates multiple cancer cell properties and plays a key role in tumorigenic processes. However, Src inhibitors as single agents have shown limited effects in solid tumors. Here, we examined the antitumor effects of the Src inhibitor dasatinib, the PARP inhibitor veliparib, and the DNA-damaging agent carboplatin in TNBC models to try and identify the combination with the most clinical potential.

Methods

Dasatinib, veliparib and carboplatin were tested in TNBC cells in vitro and in xenograft tumors in vivo.

Results

Surprisingly, treatment with the combination of veliparib plus carboplatin led to an increase in Src phosphorylation. Importantly, dasatinib attenuated Src overexpression induced by veliparib plus carboplatin and further inhibited the downstream signaling of Src. In xenograft models, the triple combination of dasatinib with veliparib plus carboplatin showed greater tumor growth inhibitory effects compared with single agents or double combinations. No systemic toxicity was observed in mice treated with the triple combination.

Conclusions

This study emphasizes the merit of evaluating the triple combination therapy, dasatinib with veliparib plus carboplatin, in TNBC clinical trials.

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Abbreviations

TNBC:

Triple-negative breast cancer

PARP:

Poly ADP ribose polymerase

HR:

Homologous recombination

IHC:

Immunohistochemistry

pCR:

Pathological complete response

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Acknowledgements

We sincerely thank National Cancer Institute for providing us drugs and we highly appreciate Avera Cancer Institute for supporting this study.

Funding

This study was supported by Avera Cancer Institute.

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Authors and Affiliations

  1. Avera Center for Precision Oncology, Avera Cancer Institute, Sioux Falls, 1000 E 23rd St., Sioux Falls, SD, 57105, USA

    Yuliang Sun, Xiaoqian Lin, Jennifer Carlson Aske, Ping Ye, Casey Williams, Mark Abramovitz & Brian R. Leyland-Jones

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  1. Yuliang Sun
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  2. Xiaoqian Lin
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  3. Jennifer Carlson Aske
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  4. Ping Ye
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Contributions

YS carried out the majority of the in vitro and in vivo experiments and drafted the article. XL performed in vitro and in vivo experiments and contributed to several figures. JA conceived critical experiments of cellular apoptosis. PY helped with Statistical analysis. CW participated in coordination of the study. MA helped draft the manuscript. BL-J and YS conceived the study and supervised all experiments. All authors read and approved the final article.

Corresponding authors

Correspondence to Yuliang Sun or Brian R. Leyland-Jones.

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Conflict of interest

Casey Williams is a consultant of Takeda, and he has received funding from Takeda, Tesaro and Pfizer. Brian Leyland-Jones is a consultant of Takeda and Tesaro. The other authors declare that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Sun, Y., Lin, X., Aske, J.C. et al. Dasatinib attenuates overexpression of Src signaling induced by the combination treatment of veliparib plus carboplatin in triple-negative breast cancer. Cancer Chemother Pharmacol 84, 1241–1256 (2019). https://doi.org/10.1007/s00280-019-03962-8

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