Department of Oncology, Xiangyang Central Hospital, Hubei University of Arts and Science, No.136, Jingzhou Road, Xiangyang, 441000, China.
Fundam Clin Pharmacol. 2021 Feb;35(1):156-164. doi: 10.1111/fcp.12574. Epub 2020 Jun 10.
Cervical cancer is the second most common malignancy in women, and the novel therapeutic treatment is needed. Abemaciclib is a FDA-approved drug for breast cancer treatment. In this work, we identified that abemaciclib has potent anti-cervical cancer activity. We demonstrate that abemaciclib is the most effective drug against human papillomavirus (HPV)-negative cervical cancer cells compared to ribociclib and palbociclib, with its IC at nanomolar concentration range. This is achieved by the inhibition of proliferation and induction of apoptosis, through specifically suppressing CDK4/6-Rb-E2F and mTOR pathways by abemaciclib in HPV-negative cervical cancer cells. Of note, the combination of abemaciclib with paclitaxel and cisplatin at sublethal concentration results in much greater efficacy than chemotherapy alone. In addition, we confirm the efficacy of abemaciclib and its combination with paclitaxel or cisplatin at the doses that are not toxic to mice in HPV-negative cervical cancer xenograft mouse model. Interestingly, we show that abemaciclib and other CDK4/6 inhibitors are not effective in targeting HPV-positive cervical cancer cells, and this is likely to be associated with the high p16 and low Rb expression in HPV-positive cervical cancer cells. Our work is the first to provide the preclinical evidence to demonstrate the potential of abemaciclib for the treatment of HPV-negative cervical cancer. The mechanism analysis highlights the therapeutic value of inhibiting CDK4/6 in HPV-negative but not HPV-positive cervical cancer.
宫颈癌是女性第二大常见恶性肿瘤，需要新的治疗方法。阿贝西利是一种已获美国食品药品监督管理局批准用于乳腺癌治疗的药物。在这项工作中，我们发现阿贝西利对宫颈癌具有很强的抗肿瘤活性。我们证明，与瑞博西利和帕博西利布相比，阿贝西利对人乳头瘤病毒（HPV）阴性宫颈癌细胞的疗效最强，其半数抑制浓度（IC）处于纳摩尔浓度范围。这是通过阿贝西利特异性抑制 CDK4/6-Rb-E2F 和 mTOR 通路，从而抑制增殖和诱导细胞凋亡来实现的。值得注意的是，阿贝西利与紫杉醇和顺铂联合应用于亚致死浓度时，其疗效明显优于单独化疗。此外，我们在 HPV 阴性宫颈癌异种移植小鼠模型中证实了阿贝西利及其与紫杉醇或顺铂联合应用在不影响小鼠的剂量下的疗效。有趣的是，我们发现阿贝西利和其他 CDK4/6 抑制剂对 HPV 阳性宫颈癌细胞无效，这可能与 HPV 阳性宫颈癌细胞中 p16 高表达和 Rb 低表达有关。我们的工作首次提供了临床前证据，证明了阿贝西利治疗 HPV 阴性宫颈癌的潜力。机制分析强调了抑制 CDK4/6 在 HPV 阴性而非 HPV 阳性宫颈癌中的治疗价值。
