The Potent Novel CDK4/6 Inhibitor TQB3616 in Hormone Receptor Positive Breast Cancer: Preclinical Characterization with in vitro and Human Tumor Xenograft Models

Abstract

Purpose

Inhibition of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (RB) pathway exerts a considerable inhibitory effect, preventing the spread and metastasis of breast cancer cells and promoting tumor regression. In this study, we examined the antitumor activity of TQB3616, a novel inhibitor of CDK4/6 activity, which showed a greater efficacy improvement in antitumor effects.

Methods

TQB3616 group, abemaciclib group and endocrine or HER-2 targeted combination therapy group were set up respectively. The effects of drugs on cell proliferation activity, cell cycle, apoptosis, downstream protein expression and gene expression of HR positive (T47D, MCF-7) and HER-2 positive (BT474, MDA-MB-361) breast cancer cell lines were studied. The antiproliferative effect of TQB3616 was also measured in vivo.

Results

TQB3616 showed a remarkable inhibitory effect on the proliferation of hormone receptor-positive breast cancer cells in vitro. In addition, TQB3616 combined with endocrine therapy or Human Epidermal Growth Factor Receptor 2 (HER2) targeted therapy showed significant synergistic antitumor activity in estrogen receptor (ER)-positive/HER2-negative or HER2-positive breast cancer. In contrast to abemaciclib, which targets the CDK4/6 pathway with proven efficacy, the oral agent TQB3616 not only induced G1 stalling, leading to a profound reduction in the level of RB protein phosphorylated at Ser807/811, but also showed enhanced tumor killing effects by promoting cell apoptosis. Oral administration of TQB3616 showed more potent antitumor activity than abemaciclib in an in vitro breast cancer xenograft model, causing significant tumor regression associated with sustained target inhibition in tumor tissue and manageable in vivo toxicity.

Conclusion

The results of this study indicate that TQB3616 is a novel CDK4/6 inhibitor, and its highly effective antitumor activity against breast cancer is expected to yield promising therapeutic effects in clinical studies.

Keywords:

• breast cancer
• endocrine therapy
• CDK inhibitors
• apoptosis
• abemaciclib

The Ethics Statement

All animal procedures were approved by Welfare and Ethics Committee of the Experimental. Animal center of the Fourth Military Medical University. The procedures conformed to the guidelines of NC3Rs ARRIVE. This study followed the Guidelines for Ethical Review of Laboratory Animal Welfare in China.

Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 81472598). The authors acknowledged the assistance of ChiaTai Tianqing Pharmaceutical Company (Jiangsu, China) for offering the chemical compounds.

Disclosure

The authors report no conflicts of interest in this work.