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03 January 2019 : Laboratory Research  

Everolimus Reverses Palbociclib Resistance in ER+ Human Breast Cancer Cells by Inhibiting Phosphatidylinositol 3-Kinase(PI3K)/Akt/Mammalian Target of Rapamycin (mTOR) Pathway

Lin Chen1BCE, Guangsheng Yang2ABCDEF, Hongming Dong2A*

DOI: 10.12659/MSM.912929

Med Sci Monit 2019; 25:77-86

Abstract

BACKGROUND: Palbociclib, a specific inhibitor of CDK4/6, has been shown to provide a survival benefit in hormone receptor-positive advanced breast cancer; however, its resistance and related mechanisms are unclear.

MATERIAL AND METHODS: In this study, we constructed palbociclib-resistant hormone receptor-positive breast cancer cells (MCF-7-P) via culturing with palbociclib for at least 6 months. Quantitative real-time PCR (qRT-PCR) and western blot were used to detect the expression of stemness markers in MCF-7-P and MCF-7 cells. Additionally, cell spheroid formation, Transwell migration, ALDH1 activity, and flow cytometry assays were performed to detect stemness and migration ability of MCF-7-P cells, and the effects of everolimus on MCF-7-P cells stemness and migration ability. Growth inhibition assay was used to examine the effect of everolimus on the sensitivity of palbociclib in MCF-7-P and MCF-7 cells.

RESULTS: MCF-7-P cells had stronger stemness and higher expression of ABCG2 and MDR1. Moreover, PI3K/Akt/mTOR signaling was hyper-activated in MCF-7-P cells. Additionally, everolimus, which is a mTOR inhibitor, attenuated MCF-7-P cells stemness and re-sensitized MCF-7-P cells to palbociclib. Importantly, everolimus enhanced the antitumor effect of palbociclib in palbociclib-sensitive hormone receptor-positive cells (MCF-7 cells).

CONCLUSIONS: These findings provide a rationale for future clinical trials of palbociclib and everolimus combination-based therapy in hormone receptor-positive breast cancer.

Keywords: Breast Neoplasms, Male, Drug Resistance, stem cell research, TOR Serine-Threonine Kinases, Breast Neoplasms, Drug Resistance, Neoplasm, Everolimus, MCF-7 cells, phosphatidylinositol 3-kinase, Piperazines, Proto-Oncogene Proteins c-akt, Receptors, Estrogen

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750