Abstract 1622: In vivo study of dasatinib in combination with veliparib plus carboplatin in triple-negative breast cancer xenograft models

Field: Pharmacology, Toxicology and Pharmaceutics (Life Sciences)

Abstract Background: Recently, poly ADP ribose polymerase (PARP) inhibitors have shown potential to increase the sensitivity of platinum-based agents in tumor cells and provide therapeutic benefit for patients with advanced malignancies in BRCA or DNA repair pathway genes altered or WT condition (Basourakos et al., 2017; Gampenrieder et al., 2017). Src, a non-receptor tyrosine kinase, is involved in the regulation of cell proliferation, survival and apoptotic ability of cancer cells (Tryfonopoulos et al., 2011; Pusztai et al., 2014). Dasatinib (D) is a short-acting dual ABL/SRC family tyrosine kinase inhibitor (TKI), which has displayed anti-proliferative and anti-metastatic effectiveness against TNBC in both preclinical and clinical studies (Finn et al., 2011). Our current study examines whether combinational inhibition of Src pathway (D) would exhibit greater antitumor activity of PARP inhibitor [veliparib (V)] plus carboplatin (C) in TNBC xenograft models with different genetic back grounds. Methodology: a) We utilized MDA-MB-231, MDA-MB-468 and SUM149PT cells for in vivo study. b) TNBC cells were implanted subcutaneously into immune-compromised mice (NCr Nu/Nu, Taconic) to generate tumor xenografts. c) We evaluated the effects on tumor growth inhibition of D (12.5 mg/kg, i.p., Qd for 4 weeks) / V (25 mg/kg, oral, Bid for 5 days) / C (40mg/kg, i.v., once) as single agent or in combinations (Chan et al., 2012; De et al., 2014). d) For IHC studies, tumor tissue sections were stained with respective antibodies for proliferation, cell survival, angiogenesis and apoptosis, including: phospho-Src, Ki-67, phospho-S6 RP, phospho-Akt, phospho-ERK, CD31, cyclin D1 and cleaved caspase3. e) Student's t test was used for data analyses. Results: We observed that 1) MDA-MB-231(KRAS/BRAF mutated) xenograft model: D alone or combined with V or C or in triple combination inhibited tumor growth, the best tumor inhibition result was induced by triple combination (p &lt; 0.004); 2) MDA-MB-468 (PTEN null) xenograft model: D alone or combined with V or C or in triple combination significantly inhibited tumor growth, the best tumor inhibition result was observed by triple combination (p &lt; 0.00006); 3) SUM149PT (BRCA1 mutated, PTEN null) xenograft model: D alone or combined with V or C or in triple combination inhibited tumor growth, and triple combination, as well as D plus C, showed greater (p &lt; 0.0025) than other combinations / single agents; 4) Single agent of D / V / C was well tolerated with less than 10% mean body weight loss compared with control groups in all models. Conclusion: Our in vivo study suggests that D may enhance the antitumor activity of PARP inhibitor plus standard cytotoxic agent in TNBC xenograft tumors with different genetic backgrounds. Immunohistochemical studies of xenograft tumor samples are ongoing, the results of which will be presented at the meeting. Citation Format: Yuliang Sun, Xiaoqian Lin, Jennifer Carlson, Pradip De, Nandini Dey, Casey Williams, Brian Leyland-Jones. In vivo study of dasatinib in combination with veliparib plus carboplatin in triple-negative breast cancer xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1622.