BKM120 and BYL719 (PI3K inhibitors) sensitize estrogen receptor positive breast cancer cells to tamoxifen
Resource
Cancer Res., 75,
Journal
Cancer Res.
Journal Issue
75
Pages
-
Date Issued
2015
Date
2015
Author(s)
Chen, I-Chun
Gao, Ming
Hsiao, Lii-Ping
Huang, Yi-Wen
Yu, Huei-Chieh
Yeh, Ling-Chiun
Cheng, Ann-Lii
Lu, Yen-Shen
Abstract
Abstract Background: Tamoxifen is currently standard first line hormonal therapy for premenopausal estrogen receptor (ER) positive metastatic breast cancer women. However, the response rate is only around 30% andprogression free survival is only around 6 months, which indicate both intrinsic resistance and acquired resistance are clinical important issues. One of the important mechanisms of hormonal therapy resistance is collateral activation of PI3K/Akt pathway. This study sought to explore whether NVP-BYL719 (a novel PI3 kinase alpha selective inhibitor) or NVP-BKM120 (a novel pan-PI3K inhibitor) may enhance the efficacy of ER positive breast cancer cells toward tamoxifen. Material and methods: Five ER positive cell lines, MCF7, T47D (PIK3CA mutant), ZR75 (PIK3CA wild type, PTEN lost), MB361 (PIK3CA mutant and HER2 amplified), and HCC1500 (PIK3CA wild type, PTEN intact) were studied. Cells and Balb/c nude mice inoculated with MCF7 cells were treated with BYL719 alone, BKM120 alone, tamoxifen alone, or either one of the PI3K inhibitors in combination with tamoxifen. Their viability was measured at 6 days with MTT assay and the combination effect was evaluated by median effect analysis. Signaling targets were determined by immunoblotting analysis. The overall survival and tumor size of the nude mice were analyzed. Results: Synergism, indicated by a combination index (CI) value <1, were seen in all five cell lines treated with BYL719 or BKM120 plus tamoxifen. By immunoblotting analysis, BYL719 alone, BKM120 alone, or either drugs in combination with tamoxifen resulted in dowregulation of the PI3K signaling pathway downstream targets, including p-AKT, p-GSK3beta, and p-p70s6k expression in MCF7 and T47D cells. When MCF7 and T47D cells were treated with tamoxifen in combination with BYL719 or BKM120, an additional increase in the subG1 population by flow cytometry analysis and increase of PARP cleavage were observed by immunoblotting analysis, indicating the increase of apoptosis cell death. When MCF7 was transfected with constitutive active (myristoylated) Akt1 construct, the inhibitory effect of BYL719 and the synergistic effect between BYL719 and tamoxifen was markedly abolished, indicating that the mechanism is mainly through the inhibition of PI3K/Akt pathway. MCF7 tumor growth in Balb/c mice was successfully slowed down by the combination of BYL719 or BKM120 with tamoxifen, as compared to that in mice treated with tamoxifen alone or control. Conclusions: Our data suggest that additional PI3K blockade might be an effective strategy to enhance therapeutic effect of tamoxifen in wild type as well as in acquired tamoxifen resistance ER positive breast cancer cell. Clinical trials along this line are warranted. (The study was supported by National Science Council grant NSC 101-2325-B-002 -059) Citation Format: I-Chun Chen, Ming Gao, Lii-Ping Hsiao, Yi-Wen Huang, Huei-Chieh Yu, Ling-Chiun Yeh, Ann-Lii Cheng, Yen-Shen Lu. BKM120 and BYL719 (PI3K inhibitors) sensitize estrogen receptor positive breast cancer cells to tamoxifen. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2670. doi:10.1158/1538-7445.AM2015-2670
SDGs