Phosphatidylinositol-3 Kinase Inhibitors, Buparlisib and Alpelisib, Sensitize Estrogen Receptor-positive Breast Cancer Cells to Tamoxifen

I-Chun Chen,Tom Wei-Wu Chen,Ling-Chun Yeh,I-Wen Huang,Ann-Lii Cheng,Li-Ping Hsiao,Yen-Shen Lu,Ching-Hung Lin,Huei-Chieh Yu

doi:10.1038/s41598-017-10555-z

Abstract

Tamoxifen is the standard first-line hormonal therapy for premenopausal women with estrogen receptor (ER)-positive metastatic breast cancer (BC). One of the crucial mechanisms underlying hormonal therapy resistance is the collateral activation of the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. We explored whether PI3K inhibitors, buparlisib and alpelisib, enhance the efficacy of tamoxifen against ER-positive BC cells. We have observed a synergism between alpelisib or buparlisib and tamoxifen in the treatment for ER-positive BC cell lines harboring different PI3K alterations. Immunoblotting analysis showed alpelisib, buparlisib, or either drug in combination with tamoxifen downregulated the PI3K downstream targets in the MCF-7 and ZR75-1 cells. In the MCF-7 cells transfected with a constitutive active (myristoylated) AKT1 construct or mutant ER, the synergistic effect between alpelisib and tamoxifen was markedly attenuated, indicating that synergism depends on AKT inhibition or normally functioning ER. Combining alpelisib or buparlisib with tamoxifen also attenuated MCF-7 tumor growth in Balb/c nude mice. Our data suggest that additional PI3K blockade might be effective in enhancing the therapeutic effect of tamoxifen in ER-positive BC and support the rationale combination in clinical trials.

Highlights

Premenopausal as compared to postmenopausal estrogen receptor (ER)-positive breast cancer (BC) patients[15]
The combination of alpelisib and tamoxifen exhibited a synergistic effect at fraction affected (Fa) 0.5 on both PIK3CA mutant (MCF-7 and T47D, Fig. 1A,B) and PTEN loss (ZR75-1, Fig. 1C) cell lines with a combination index
Our study reveals the synergistic effect of combining phosphatidylinositol-3 kinase (PI3K) inhibitors with tamoxifen, as indicated by a median effect analysis in vitro and by remarkable tumor shrinkage in an MCF-7 xenograft model

Summary

Introduction

Long-term exposure to tamoxifen upregulates the PI3K pathway (11), and this partially contributes to tamoxifen resistance[12, 13, 16]. Clark et al has demonstrated that a PI3K inhibitor, LY294002, can potentiate tamoxifen-induced apoptosis in ER-positive cells[17]. Targeting the PI3K pathway might be a reasonable strategy to treat premenopausal ER-positive MBC18. Buparlisib (BKM120) is a pan-PI3K inhibitor capable of blocking all class I PI3Ks19 and reducing secondary messenger production, resulting in cell growth inhibition[19, 20]. Alpelisib (BYL719) is a p110α-specific PI3K inhibitor[21] with more favorable safety profiles than buparlisib[21]. We investigated the sensitization effect of adding PI3K inhibitors to tamoxifen to mimic the treatment of ER-positive BC in premenopausal women

Methods

Results

Conclusion