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

Abstract

// Masafumi Iida 1 , 2 , Misato Nakamura 1 , Emi Tokuda 1 , Daichi Toyosawa 1 , Toshifumi Niwa 1 , Noriaki Ohuchi 2 , Takanori Ishida 2 and Shin-ichi Hayashi 1 1 Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, Sendai, Japan 2 Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Japan Correspondence to: Masafumi Iida, email: m.iida@med.tohoku.ac.jp Keywords: breast cancer; CDK4/6 inhibitor; resistance; CDK6; p21 Received: March 01, 2019     Accepted: July 21, 2019     Published: August 06, 2019 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.