Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with the 2018 ASCO Annual Meeting but not presented at the Meeting, can be found online only.
Antitumor effect and mechanisms research of the PARP inhibition combination with platinum salts and PI3K inhibition on human triple negative breast cancer cell.
2018 ASCO Annual Meeting
J Clin Oncol 36, 2018 (suppl; abstr e12535)
Author(s): Jin Zhang; Breast Cancer Center, Tianjin, China
Background: TNBC is a heterogeneous group of tumors with more aggressive clinical features. Platinum salts have demonstrated sufficient efficacy and safety for consideration of their use for TNBC. Olaparib is an oral inhibitor of PARP that, blocks base-excision repair by trapping PARP at sites of DNA damage, leading to the collapse of DNA replication forks and the accumulation of DNA double-strand breaks. BKM120, a PI3K inhibitor has demonstrated anti-proliferative, pro-apoptotic, and anti-tumor activity in a variety of cell lines and xenograft models from cancers with and without aberrant PI3K pathway activation. However, the effects of combination of the three drugs on triple-negative breast cancer have not yet been elucidated. Methods: MTT assays and drug resistance clonogenic assays were performed to evaluate the cell viability in response to drug treatments alone and defined the combined measurements of three kinds of drugs. We used Flow cytometric analysis to evaluate cell cycle and cell apoptptic changes. The expression levels of γ-H2aX and PADPR were assessed by western blot to detection of DNA damage levels due to the three drug action. The expression levels of 53BP1, p-ATM, p-AKT and p53 were assessed by western blot to exam the proportion of DNA repair by non homologous terminal junction pathway. We also tested the level of p21 and p27 to exam whether drugs influence the cell cycle. Results: While combination of the three drugs in a very low dose was determined more effective than each one alone, strong synergistic antiproliferative effects were observed, meanwhile which was well tolerated when treated in MDA-10A cell line.Apoptotic assay, cell cycle assay and western blot proved that the combined killing effects of three drugs were performed on DNA damage, which Non-homologous end joining(NHEJ) repair was enhanced and HR repair was inhibited. Conclusions: This suggests a strong rationale to explore the therapeutic strategy of using carboplatin in combination of Olaparib and BKM120 for triple-negative breast cancer patients, and expand the olaparib drug population.
1. TAILORx: Phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score.