胸膜弥漫性胸膜间皮瘤 (DPM) 是一种高度侵袭性且难治性的癌症，与石棉接触有关。尽管采用多种模式治疗，DPM 患者的预后仍然很差，诊断后平均生存期为 2 年。顺铂是一种铂类化疗药物，常用于治疗 DPM。然而，顺铂耐药性的发展极大地限制了其有效性，凸显了对替代治疗策略的迫切需要。新型选择性细胞周期蛋白依赖性激酶 4 和 6 (CDK4/6) 抑制剂通过抑制细胞周期进程和抑制肿瘤生长，在多种恶性肿瘤中显示出良好的前景。最近的研究表明 abemaciclib 用于 DPM 治疗的潜力，一项 II 期临床试验已显示出初步令人鼓舞的结果。在这里，我们在一组 DPM 细胞系和非肿瘤间皮细胞 (MET-5A) 上测试了 abemaciclib、palbociclib 和 ribociclib ) 细胞。具体而言，我们重点关注 abemaciclib，它是对所有测试的 DPM 细胞系最有效的细胞毒剂。 Abemaciclib 降低了 DPM 细胞活力、克隆形成潜力和生长为三维 (3D) 球体的能力。此外，abemaciclib 诱导延长作用，从而损害第二代球体形成并诱导 G0/G1 停滞和细胞凋亡/坏死。有趣的是，RB 家族成员的单一沉默不会损害细胞对 abemaciclib 的反应，这表明它们可能在触发 abemaciclib 的细胞抑制作用方面相互补充。有趣的是，abemaciclib 减少了 AKT 的磷酸化，AKT 在 DPM 中高度活跃，并与药理学 AKT 抑制剂 (AKTi VIII) 具有协同作用。 Abemaciclib 还与顺铂具有协同作用，降低了对顺铂产生耐药性的 DPM 细胞的活力。总体而言，我们的结果表明，应进一步探索单独使用 CDK4/6 抑制剂或与标准护理联合使用的 DPM 治疗。版权所有 © 2024 Costa, Forte 、彭蒂马利、伊安努齐、阿尔法诺、卡彭、卡梅林戈、卡拉布雷斯、冯·阿尔克斯、贝诺特·多明格斯、昆蒂利亚尼、德·劳伦蒂斯、莫里昂和佐丹奴。

Diffuse pleural mesothelioma (DPM) of the pleura is a highly aggressive and treatment-resistant cancer linked to asbestos exposure. Despite multimodal treatment, the prognosis for DPM patients remains very poor, with an average survival of 2 years from diagnosis. Cisplatin, a platinum-based chemotherapy drug, is commonly used in the treatment of DPM. However, the development of resistance to cisplatin significantly limits its effectiveness, highlighting the urgent need for alternative therapeutic strategies. New selective inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have shown promise in various malignancies by inhibiting cell cycle progression and suppressing tumor growth. Recent studies have indicated the potential of abemaciclib for DPM therapy, and a phase II clinical trial has shown preliminary encouraging results.Here, we tested abemaciclib, palbociclib, and ribociclib on a panel of DPM cell lines and non-tumor mesothelial(MET-5A) cells.Specifically, we focused on abemaciclib, which was the mosteffective cytotoxic agent on all the DPM cell lines tested. Abemaciclib reduced DPM cell viability, clonogenic potential, and ability to grow as three-dimensional (3D) spheroids. In addition, abemaciclib induced prolonged effects, thereby impairing second-generation sphere formation and inducing G0/G1 arrest and apoptosis/ necrosis. Interestingly, single silencing of RB family members did not impair cell response to abemaciclib, suggesting that they likely complement each other in triggering abemaciclib's cytostatic effect. Interestingly, abemaciclib reduced the phosphorylation of AKT, which is hyperactive in DPM and synergized with the pharmacological AKT inhibitor (AKTi VIII). Abemaciclib also synergized with cisplatin and reduced the viability of DPM cells with acquired resistance to cisplatin.Overall, our results suggest that CDK4/6 inhibitors alone or in combination with standard of care should be further explored for DPM therapy.Copyright © 2024 Costa, Forte, Pentimalli, Iannuzzi, Alfano, Capone, Camerlingo, Calabrese, von Arx, Benot Dominguez, Quintiliani, De Laurentiis, Morrione and Giordano.