Metformin-induced caveolin-1 expression promotes T-DM1 drug efficacy in breast cancer cells

Yuan-Chiang Chung,Wei-Ting Chao,Ching-Ming Chang,Ting-Wei Chang,Wan-Chen Wei,King-Jen Chang

doi:10.1038/s41598-018-22250-8

Yuan-Chiang Chung, Wei-Ting Chao + Show 4 more

Open Access

https://doi.org/10.1038/s41598-018-22250-8

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Abstract

Trastuzumab emtansine (T-DM1) is an antibody drug conjugate (ADC) that was recently approved for the treatment of HER-2-positive metastatic breast cancer. The drug sensitivity of ADCs depends mainly on the internalization efficiency of the drug. Caveolin-1 was shown to promote T-DM1 internalization and enhance drug sensitivity. Whether caveolin-1 can be overexpressed to improve T-DM1 efficacy is interesting and has the potential for clinical application. In this study, diabetes drug metformin was investigated in terms of induction of caveolin-1 expression for increased efficacy of subsequent T-DM1 application. BT-474 cells were pretreated with metformin, followed by combined therapy with metformin and T-DM1. The T-DM1 internalization and drug efficacy were determined, and the protein expressions for signal transduction were also monitored. Caveolin-1 shRNA was applied to suppress endogenous caveolin-1 expression, and the ability of metformin to promote T-DM1 efficacy was investigated. Result showed that in BT-474 cells pretreated with metformin, cellular caveolin-1 overexpression was induced, which then promoted drug efficacy by enhancing T-DM1 internalization. As cellular caveolin-1 was suppressed by shRNA, the effect of metformin-enhanced T-DM1 cytotoxicity was decreased. This study demonstrated that metformin can be applied prior to T-DM1 treatment to improve the clinical efficacy of T-DM1 by enhancing caveolin-1-mediated endocytosis.

Highlights

IntroductionTrastuzumab emtansine (trastuzumab-DM1; T-DM1) was recently developed as a new-generation target drug for breast cancer
Trastuzumab emtansine was recently developed as a new-generation target drug for breast cancer
BT-474 cells were treated with trastuzumab, which up-regulated the overexpression of caveolin-1 peaking at around 12–24 hours (Fig. 1A)

Summary

Introduction

Trastuzumab emtansine (trastuzumab-DM1; T-DM1) was recently developed as a new-generation target drug for breast cancer. Recent studies demonstrated that caveolin-1, a 21KD membrane protein that plays a role in endocytosis and vesicle trafficking, is co-localized with trastuzumab to promote T-DM1 internalization and enhance drug efficacy[8,9]. T-DM1 was reported to exert a significant benefit in terms of survival in patients with HER-2-positive advanced breast cancer previously treated with trastuzumab and a taxane in a second-line study[3]. In the recent MARIANNE trial[10], the progression-free survival (PFS) under T-DM1 treatment was found to be non-inferior, but not superior, to trastuzumab plus a taxane as the first-line treatment for local advanced or metastatic breast cancer. Treatment with trastuzumab or taxanes in breast cancer cells to obtain a greater beneficial effect of T-DM1 treatment was assessed in the current study. Our study assessed the caveolin-1 expression upon treatment with metformin, and the drug efficacy of T-DM1 after caveolin-1 induction was determined

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