CDK4/6抑制劑阻礙胰腺癌化療恢復(fù)
2020-02-29
來(lái)源：小柯機(jī)器人
西班牙國(guó)立癌癥研究中心Marcos Malumbres、Manuel Hidalgo、美國(guó)輝瑞公司David J. Shields等研究人員合作發(fā)現(xiàn)，CDK4/6抑制劑可阻礙胰腺癌從細(xì)胞毒性化療中恢復(fù)。該項(xiàng)研究成果于2020年2月27日在線發(fā)表在《癌細(xì)胞》雜志上。
研究人員發(fā)現(xiàn)，紫杉烷類藥物后順序給藥CDK4/6抑制劑可防止胰腺導(dǎo)管腺癌（PDAC）細(xì)胞、患者來(lái)源異種移植物和基因工程改造的小鼠中的細(xì)胞增殖，并經(jīng)常在PDAC中觀察到Kras G12V和Cdkn2a-null突變。
這種作用與CDK4/6抑制劑對(duì)從染色體損傷中恢復(fù)所需的同源重組蛋白的抑制活性有關(guān)。CDK4/6抑制劑還阻止癌細(xì)胞從多種破壞DNA的藥物中恢復(fù)，這表明在可用化學(xué)治療藥物后其順序給藥具有廣泛的適用性。
據(jù)悉，目前，抑制細(xì)胞周期激酶CDK4和CDK6已成為晚期乳腺癌標(biāo)準(zhǔn)治療的一部分。但是，CDK4/6抑制劑被認(rèn)為不會(huì)與DNA損傷或抗有絲分裂化學(xué)療法配合使用，因?yàn)榍罢邥?huì)阻止細(xì)胞周期進(jìn)入，從而干擾S期或有絲分裂靶向藥物。
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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