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

Abstract

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. Dasatinib, veliparib and carboplatin were tested in TNBC cells in vitro and in xenograft tumors in vivo. 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. This study emphasizes the merit of evaluating the triple combination therapy, dasatinib with veliparib plus carboplatin, in TNBC clinical trials.