Abstract 4417: In vitro efficacy of dasatinib alone or in combination with PARP inhibitor plus standard cytotoxic agent in triple-negative breast cancer cell lines

Abstract

Abstract Background: Patients presenting with triple-negative breast cancer (TNBC) have the poorest prognosis of all breast cancer (BC) subtypes and there are limited treatment options, with no efficacious targeted therapies. Therefore, improved approaches to treatment of these cancers are an unmet need. Several molecular targets including: epidermal growth factor receptor (EGFR), poly ADP ribose polymerase (PARP), and Src family tyrosine kinases are under clinical investigation for the treatment of this disease (De et al., 2014; Kim et al., 2013). Src family tyrosine kinases play a critical role in signal transduction downstream of growth factor receptors and integrin family members. Preclinical studies have established a role for Src family kinases in proliferation, angiogenesis and invasion in prostate cancer model (Varcaris et al., 2014). Dasatinib is an rally-active ATP-competitive small molecule kinase inhibitor that potently inhibits Abl kinase, Src family kinases and other kinases (Lombardo et al., 2004), and has shown its anti-proliferative and anti-metastatic effectiveness against TNBC in both preclinical and clinical studies (Finn et al., 2011). Recently, PARP inhibitors in combination with chemotherapy have shown promising results in TNBC in clinical and preclinical studies (Tutt et al., 2010; De et al., 2014). We hypothesize that the inhibitor of Src family of kinases (dasatinib) in combination with PARP inhibitor (ABT888) plus standard cytotoxic agent (carboplatin) will attenuate the growth of TNBC cell lines. Methodology: BT-20 (PIK3CA mutated, H1047R), HCC70 (PTEN null), HCC1937 (PTEN null), MDA-MB-231 (KRAS/BRAF mutated), MDA-MB-468 (PTEN null) and SUM149PT (BRCA1 mutated, PTEN null) cells were used for this study. Growth inhibition, survival/proliferation, colony formation and apoptosis were examined using MTT assay, 2D proliferative/growth assay, 3D-ON-TOP assays, and annexinV staining respectively. Results: Our data showed that 1) High anti-proliferative activities were observed following the treatment of dasatinib along with ABT888 plus carboplatin in both 2D proliferation assay and 3D-ON TOP colony formation assay. 2) In the same line, dasatinib in combination with ABT888 plus carboplatin inducing early stage apoptosis was seen by Annexin V staining in all tested cell lines. 3) Our MTT data showed that anti-proliferative activity of dasatinib as a single agent is highly variable in different genetic background of TNBC cell lines. Conclusion: Our data suggest that the combination of Src inhibitor may enhance the antitumor activity of PARP inhibitor plus standard cytotoxic agent in TNBC models. Mechanistic studies are ongoing, the results of which will be presented in the meeting. Citation Format: Yuliang Sun, Jennifer Carlson, Xiaoqian Lin, Pradip De, Casey Williams, Sally Hausman, Nandini Dey, Brian Leyland-Jones. In vitro efficacy of dasatinib alone or in combination with PARP inhibitor plus standard cytotoxic agent in triple-negative breast cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4417.