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 IC₅₀ 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.

中文翻译：

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Abemaciclib 通过特异性抑制 CDK4/6-Rb-E2F 和 mTOR 通路使 HPV 阴性宫颈癌对化疗敏感

宫颈癌是女性第二常见的恶性肿瘤，需要新的治疗方法。Abemaciclib 是 FDA 批准的用于治疗乳腺癌的药物。在这项工作中，我们发现 abemaciclib 具有有效的抗宫颈癌活性。我们证明，与 ribociclib 和 palbociclib 相比，abemaciclib 是对抗人乳头瘤病毒 (HPV) 阴性宫颈癌细胞最有效的药物，其 IC ₅₀在纳摩尔浓度范围内。这是通过抑制增殖和诱导细胞凋亡，通过 abemaciclib 在 HPV 阴性宫颈癌细胞中特异性抑制 CDK4/6-Rb-E2F 和 mTOR 通路来实现的。值得注意的是，亚致死浓度的 abemaciclib 与紫杉醇和顺铂的组合比单独的化学疗法产生更大的疗效。此外，我们在 HPV 阴性宫颈癌异种移植小鼠模型中确认了 abemaciclib 及其与紫杉醇或顺铂组合的疗效，剂量对小鼠无毒。有趣的是，我们发现 abemaciclib 和其他 CDK4/6 抑制剂不能有效靶向 HPV 阳性宫颈癌细胞，这可能与 HPV 阳性宫颈癌细胞中的高 p16 和低 Rb 表达有关。我们的工作是第一个提供临床前证据来证明 abemaciclib 治疗 HPV 阴性宫颈癌的潜力的工作。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。