Abstract P6-15-04: Targeting the PI3K Pathway Enhances the Effect of PARP-1 Inhibition in BRCA1 Deficient Breast Cancer Cells

Abstract

Abstract Background: Available targeted therapies have improved the prognosis for many women diagnosed with breast cancer. However, more than 15% of cases do not benefit from these targeted agents. Amongst these are tumours with Breast cancer 1 (BRCA1) dysfunction, triple-negative and basal-like breast cancers, which remain a treatment challenge and are associated with a poor outcome. New approaches to specifically target these groups of breast tumors are needed. The DNA damage repair defects associated with lack of BRCA1 confers sensitivity to poly-(ADP-ribose) polymerase 1 (PARP-1) inhibitors. Furthermore, most BRCA1 mutated tumours do not express the phosphatase and tensin homolog (PTEN) implying activation of the phosphatidylinositol-3 kinase (PI3K) pathway which promotes cell survival and resistance to apoptosis. The aim of this study was to investigate if co-targeting the PI3K pathway can improve the response of BRCA1 mutated cells to PARP-1 inhibition. Material and methods:, Two BRCA1 and PTEN deficient breast cancer cell lines; MDA-MB-436 and SUM149, were treated with the PARP-1 inhibitor AG14361 (1-(4-dimethylaminomethyl-phenyl)-8-9-dihydro-7H-2,7,9a-benzo[cd]azulen-6-one) and the PI3K inhibitor LY294002 (2-(4-morpholinyl)-8-phenyl-chromone), as single agents and in combination. Cytotoxicity was estimated using the sulpho-rhodamine B assay while cell cycle phase distribution and DNA integrity were analyzed by flow cytometry. Results: AG14361 induced DNA damage leading to G2/M arrest and decreased viability. LY294002, on the other hand, affected the cell cycle by arresting cells in G1. Importantly, combining AG14361 with LY294002 further decreased survival (P<0.001) with a concomitant decrease in G2/M (P<0.05). Discussion: This observation may indicate a combination specific up-regulation of apoptosis and suggests that LY294002 potentiates the effects of AG14361. Our results may represent an improved selective targeted treatment strategy for BRCA1 deficient breast cancers and other cancers with DNA damage repair defects and activated PI3K signalling. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-04.