The p21 levels have the potential to be a monitoring marker for ribociclib in breast cancer.

Emi Tokuda,Noriaki Ohuchi,Shin-Ichi Hayashi,Toshifumi Niwa,Masafumi Iida,Takanori Ishida,Daichi Toyosawa,Misato Nakamura

doi:10.18632/oncotarget.27127

Abstract

Although cyclin-dependent kinase (CDK) 4/6 inhibitors have exhibited remarkable results for patients with estrogen receptor (ER)–positive breast cancer in clinical trials, the mechanism of CDK4/6 inhibitor resistance remains unclear. Thus, this study aimed to investigate the mechanism of CDK4/6 inhibitor resistance using two CDK4/6 inhibitor resistant breast cancer cell lines. We established CDK6 overexpressed cell lines (MCF7-C6) from MCF-7 cells using the stably transfected CDK6 expression vector. Additionally, acquired ribociclib-resistant (RIBR) cell lines were created using ER-positive hormone-resistant cell lines by long-term exposure to ribociclib. CDK6 overexpression and the knockdown of CDK4 experiments highlight the significance of high levels of CDK4 and low levels of CDK6 in CDK4/6 inhibitor sensitivity. Moreover, RIBR cell lines did not exhibit incremental CDK6 compared with ER-positive hormone-resistant cell lines. In MCF7-C6 and RIBR cell lines, p21 levels decreased, and p21 levels were proportional to CDK4/6 inhibitor sensitivity. This study suggests that overexpression of CDK6 is one of the many possible mechanisms of resistance to CDK4/6 inhibitors. Furthermore, p21 levels have the potential to serve as a marker for CDK4/6 inhibitors independent of the resistance mechanism.

Highlights

Until recently, the primary therapeutic options for postmenopausal women with estrogen receptor (ER)– positive human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) were predominantly comprised of hormonal therapy [1, 2]
These findings suggested a possible correlation between the ribociclib sensitivity and the CDK4 and CDK6 expression levels
P21 expression levels were markedly reduced in both MCF7-C6 and RIBR cell lines, while CDK2 and cyclin E1 expression remained almost unchanged. These changes in RIBR cell lines were not observed during short-term (24-h) exposure of ribociclib to EDR1 (Figure 4D, indicated by an arrow). These findings revealed that MCF7-C6 and RIBR cell lines expressed low levels of p21, the resistance mechanisms to CDK4/6 inhibitors were different

Summary

Introduction

The primary therapeutic options for postmenopausal women with estrogen receptor (ER)– positive human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) were predominantly comprised of hormonal therapy [1, 2]. We researched the mechanism of aromatase inhibitor (AI) resistance by establishing multiple AI-resistant breast cancer cell line models and reporting on several mechanisms of AI resistance [3,4,5,6]. Hormonal therapy resistance is considered a critical problem and is correlated with the involvement of intracellular phosphorylation pathways, such as the PI3K–AKT–mTOR pathway and MAPK pathways [7, 8]. We reported that driver signaling escapes to MAPK signaling despite the suppression of mTOR signaling [9]. Breast cancer cells struggle to survive by altering the driver pathway. Targeting downstream signaling of ER and intracellular phosphorylation pathways (i.e. the cell cycle) is a logical, rational strategy for breast cancer drug therapy

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Conclusion