CDK4/6抑制剂阻碍胰腺癌化疗恢复
西班牙国立癌症研究中心Marcos Malumbres、Manuel Hidalgo、美国辉瑞公司David J. Shields等研究人员合作发现，CDK4/6抑制剂可阻碍胰腺癌从细胞毒性化疗中恢复。该项研究成果于2020年2月27日在线发表在《癌细胞》杂志上。
研究人员发现，紫杉烷类药物后顺序给药CDK4/6抑制剂可防止胰腺导管腺癌（PDAC）细胞、患者来源异种移植物和基因工程改造的小鼠中的细胞增殖，并经常在PDAC中观察到Kras G12V和Cdkn2a-null突变。
这种作用与CDK4/6抑制剂对从染色体损伤中恢复所需的同源重组蛋白的抑制活性有关。CDK4/6抑制剂还阻止癌细胞从多种破坏DNA的药物中恢复，这表明在可用化学治疗药物后其顺序给药具有广泛的适用性。
据悉，目前，抑制细胞周期激酶CDK4和CDK6已成为晚期乳腺癌标准治疗的一部分。但是，CDK4/6抑制剂被认为不会与DNA损伤或抗有丝分裂化学疗法配合使用，因为前者会阻止细胞周期进入，从而干扰S期或有丝分裂靶向药物。
附：英文原文
Title: CDK4/6 Inhibitors Impair Recovery from Cytotoxic Chemotherapy in Pancreatic Adenocarcinoma
Author: Beatriz Salvador-Barbero, Mónica álvarez-Fernández, Elisabet Zapatero-Solana, Aicha El Bakkali, María del Camino Menéndez, Pedro P. López-Casas, Tomas Di Domenico, Tao Xie, Todd VanArsdale, David J. Shields, Manuel Hidalgo, Marcos Malumbres
Issue&Volume: 2020-02-27
Abstract: Inhibition of the cell-cycle kinases CDK4 and CDK6 is now part of the standard treatmentin advanced breast cancer. CDK4/6 inhibitors, however, are not expected to cooperatewith DNA-damaging or antimitotic chemotherapies as the former prevent cell-cycle entry,thus interfering with S-phase- or mitosis-targeting agents. Here, we report that sequentialadministration of CDK4/6 inhibitors after taxanes cooperates to prevent cellular proliferationin pancreatic ductal adenocarcinoma (PDAC) cells, patient-derived xenografts, andgenetically engineered mice with Kras G12V and Cdkn2a-null mutations frequently observed in PDAC. This effect correlates with the repressiveactivity of CDK4/6 inhibitors on homologous recombination proteins required for therecovery from chromosomal damage. CDK4/6 inhibitors also prevent recovery from multipleDNA-damaging agents, suggesting broad applicability for their sequential administrationafter available chemotherapeutic agents.
DOI: 10.1016/j.ccell.2020.01.007
Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30046-5
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