Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan, 442000, China.
Department of Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China.
Curr Med Sci. 2023 Oct;43(5):927-934. doi: 10.1007/s11596-023-2789-3. Epub 2023 Sep 27.
Aberrant activating mutations in cyclin-dependent kinases 4 and 6 (CDK4/6) are common in various cancers, including gastroesophageal malignancies. Although CDK4/6 inhibitors, such as abemaciclib and palbociclib, have been approved for breast cancer treatment, their effectiveness as a monotherapy remains limited for gastroesophageal tumors. The present study explored the underlying mechanism of abemaciclib resistance.
Abemaciclib-resistant gastric cancer cell lines were generated, and the phospho-eukaryotic translation initiation factor 4E (p-eIF4E) and eIF4E expression was compared between resistant and parental cell lines. In order to analyze the role of eIF4E in cell resistance, siRNA knockdown was employed. The effectiveness of ribavirin alone and its combination with abemaciclib was evaluated in the gastric cancer xenograft mouse model.
The upregulation of eIF4E was a common feature in gastric cancer cells exposed to prolonged abemaciclib treatment. Gastric cancer cells with increased eIF4E levels exhibited a better response to eIF4E inhibition, especially those that were resistant to abemaciclib. Ribavirin, which is an approved anti-viral drug, significantly improved the efficacy of abemaciclib, both in vitro and in vivo, by inhibiting eIF4E. Importantly, ribavirin effectively suppressed the abemaciclib-resistant gastric cancer growth in mice without causing toxicity.
These findings suggest that targeting eIF4E can enhance the abemaciclib treatment for gastric cancer, proposing the potential combination therapy of CDK4/6 inhibitors with ribavirin for advanced gastric cancer.
细胞周期蛋白依赖性激酶 4 和 6（CDK4/6）的异常激活突变在包括胃食管恶性肿瘤在内的各种癌症中很常见。尽管 CDK4/6 抑制剂，如 abemaciclib 和 palbociclib，已被批准用于乳腺癌治疗，但它们作为单一疗法对胃食管肿瘤的疗效仍然有限。本研究探讨了 abemaciclib 耐药的潜在机制。
生成 abemaciclib 耐药的胃癌细胞系，并比较耐药和亲本细胞系之间的磷酸化真核翻译起始因子 4E（p-eIF4E）和 eIF4E 表达。为了分析 eIF4E 在细胞耐药中的作用，采用 siRNA 敲低。单独使用利巴韦林及其与 abemaciclib 的联合治疗在胃癌异种移植小鼠模型中进行了评估。
在长期暴露于 abemaciclib 治疗的胃癌细胞中，eIF4E 的上调是一个共同特征。eIF4E 水平升高的胃癌细胞对 eIF4E 抑制的反应更好，尤其是对 abemaciclib 耐药的细胞。利巴韦林是一种已批准的抗病毒药物，通过抑制 eIF4E，显著提高了 abemaciclib 的疗效，无论是在体外还是在体内。重要的是，利巴韦林在不引起毒性的情况下有效抑制了 abemaciclib 耐药的胃癌在小鼠中的生长。
这些发现表明，靶向 eIF4E 可以增强 abemaciclib 治疗胃癌的效果，为晚期胃癌的 CDK4/6 抑制剂与利巴韦林联合治疗提供了潜在的治疗方案。
