CDK4/6 Inhibitor Can Improve Niraparib Sensitivity and Reverse Acquired Drug Resistance Through Endonuclease G Nuclear Translocation in BRCA Wild‐Type Ovarian Cancer: A Vitro Study

ABSTRACT Objective To investigate whether the CDK4/6 inhibitor TQB‐3616 has synergistic effects with niraparib ZL‐2306 in suppressing BRCA wild‐type ovarian cancer and to explore the mechanisms of combined therapy. Design In vitro study. Setting Laboratory of a tertiary hospital and Experimental Animal Centre of Shanghai Jiaotong University School of Medicine. Sample SKOV3 (human ovarian cancer cell line). Methods The BRCA wild‐type ovarian cancer cell line, SKOV3, was used, and the niraparib‐resistant cell line (SKOV3‐NR) was generated using a concentration‐increasing method. The effects of combined therapy with TQB‐3616 and ZL‐2306 on cell viability, long‐term survival, apoptosis and cell cycle were studied in vitro and in vivo, and DNA damage was detected. Proteomic mass spectrometry was performed to determine the mechanism of action underlying combined therapy. Main Outcome Measure CDK4/6 and niraparib efficacy. Results A niraparib‐resistant strain of the wild‐type BRCA ovarian cancer cell line SKOV3 was generated, and the CDK4/6 inhibitor TQB‐3616 was combined with niraparib ZL‐2306 to inhibit the growth of ovarian cancer cells and reverse drug resistance. The feasibility and effectiveness of ZL‐2306 in combination with TQB‐3616 were demonstrated in a tumour‐bearing nude mouse model. Conclusions Combined therapy with the CDK4/6 inhibitor TQB‐3616 and niraparib ZL‐2306 showed synergistic antitumour effects against BRCA wild‐type ovarian cancer without increasing the toxicity of each drug. The antitumour effect may be related to mitochondrial apoptosis, where EndoG nuclear translocation plays a critical role. This study proposes combined therapy of CDK4/6 and PARP inhibitors as a novel approach for the treatment of refractory ovarian cancer.