与BEZ235联合治疗可增强BRCA1阴性乳腺癌细胞对奥拉帕尼的敏感性。

Co-treatment with BEZ235 Enhances Sensitivity of BRCA1-negative Breast Cancer Cells to Olaparib.

作者信息

Yi Yong Weon, Park Jeong-Soo, Kwak Sahng-June, Seong Yeon-Sun

机构信息

Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, U.S.A. Department of Nanobiomedical Science & BK21 PLUS Research Center for Regenerative Medicine, Dankook University, Cheonan, Chungnam, Republic of Korea.

Department of Biochemistry, College of Medicine, Dankook University, Cheonan, Chungnam, Republic of Korea.

出版信息

Anticancer Res. 2015 Jul;35(7):3829-38.

PMID:26124328

Abstract

The poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib has been reported as having preferential anti-proliferative effects on breast cancer 1 (BRCA1)-deficient breast and ovarian cancer cells and was recently approved by the US Food and Drug Administration (FDA) for advanced, BRCA1-mutated ovarian cancer. Herein, we show that BEZ235, a protein kinase inhibitor, enhanced the tumor cell-killing effect of olaparib in BRCA1-mutated breast cancer cells in vitro. BEZ235 reduced olaparib-induced phosphorylation of p53 binding protein 1 (53BP1) and 53BP1 foci formation, as well as phosphorylation of AKT (S473). Long-term colony-formation assay revealed more strong synergistic effects of this combination in SUM149PT and MDA-MB-468 breast cancer cell lines. BEZ235 treatment combined with olaparib may be a candidate for effective therapeutic treatment of BRCA1-mutated breast cancer.

摘要

聚（ADP - 核糖）聚合酶（PARP）抑制剂奥拉帕尼已被报道对乳腺癌1（BRCA1）缺陷的乳腺癌和卵巢癌细胞具有优先的抗增殖作用，并且最近被美国食品药品监督管理局（FDA）批准用于晚期BRCA1突变的卵巢癌。在此，我们表明蛋白激酶抑制剂BEZ235在体外增强了奥拉帕尼对BRCA1突变乳腺癌细胞的肿瘤细胞杀伤作用。BEZ235减少了奥拉帕尼诱导的p53结合蛋白1（53BP1）的磷酸化和53BP1灶形成，以及AKT（S473）的磷酸化。长期集落形成试验显示这种组合在SUM149PT和MDA - MB - 468乳腺癌细胞系中具有更强的协同作用。BEZ235与奥拉帕尼联合治疗可能是BRCA1突变乳腺癌有效治疗的候选方案。