Abstract P6-15-05: A Cyclin-Dependent Kinase Inhibitor P276 Inhibits Growth of Breast Cancer Cell Lines Including Basal-Type/Triple-Negative Alone and in Combination with Chemotherapeutic Drugs

Abstract

Abstract Background: Development of novel agents and drug combinations are urgently needed for the treatment of breast cancer especially triple negative breast cancer (TNBC). P276 is a potent cyclin-dependent kinase inhibitor with excellent antiproliferative activity against various human cancer cell lines. Here, we report the activity of P276, as a single agent and in combination with paclitaxel or gemcitabine/carboplatin in TNBC cell lines. Material and Methods: In vitro effect of P276 on breast cancer cell lines was determined by cytotoxicity assay, flow cytometry, western blotting and immunofluorescence studies. The antiangiogenic potential of P276 was evaluated using HIF-1 a and VEGF inhibition assay, wound healing and tube formation. In vivo efficacy was studied using human xenograft models in SCID and nude mice. Results: Human breast cancer cell lines including TNBC, treated with P276 were found to be highly susceptible with IC50 ranging from 0.3 to 1.0 mM. In MCF-7 (Her2-, BRCA+/−) and MDA-MB-231 (ER-, PR-, Her2-). P276 significantly down regulated cell cycle proteins pRbser780, cyclin D1, Cdk4 and antiapoptotic protein Bcl-2 followed by 80-85% apoptosis. P276 treatment also lead to the inhibition of PARP enzyme activity or PARP cleavage depending on the cell type. Interestingly, P276 inhibited the key angiogenic mediators HIF-1 a and VEGF with IC50 of 0.095mM and 0.31mM respectively in reporter gene based assays. These antiangiogenic effects were confirmed by immunofluorescence and migration studies in TNBC cell lines and endothelial tube formation. In breast cancer patient derived tumor cell line MAXF 401 (basal like) xenografts in nude mice, cyclical dosing of P276 showed growth inhibition of 71%. Moreover, combination studies of P276 with paclitaxel or gemcitabine plus carboplatin showed synergistic effect in TNBC cell lines. Discussion: Our studies provide compelling evidence for the clinical development of P276 for the treatment of triple negative breast cancer either as monotherapy or in combination with paclitaxel or gemcitabine/carboplatin. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-05.