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CLIN CANCER RES：靶向PI3Kδ治疗成熟B细胞恶性肿瘤

2018-03-08 MedSci MedSci原创

成熟B细胞恶性肿瘤PI3Kδ靶向治疗
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B细胞受体（BCR）异常活动与成熟B细胞肿瘤发病密切相关，这一概念已被BCR相关酶BTK和PI3Kδ抑制剂的临床成功部分验证。这些抑制剂也存在缺陷，包括完全反应不足，获得性耐药和毒性。CLIN CANCER RES近期发表了一篇文章，研究cyclic-AMP/PDE4信号通路抑制PI3K机制，寻找在该机制基础上的联合策略治疗成熟B细胞恶性肿瘤。

B细胞受体（BCR）异常活动与成熟B细胞肿瘤发病密切相关，这一概念已被BCR相关酶BTK和PI3Kδ抑制剂的临床成功部分验证。这些抑制剂也存在缺陷，包括完全反应不足，获得性耐药和毒性。CLIN CANCER RES近期发表了一篇文章，研究cyclic-AMP/PDE4信号通路抑制PI3K机制，寻找在该机制基础上的联合策略治疗成熟B细胞恶性肿瘤。

作者使用弥漫大B细胞淋巴瘤细胞系和原发慢性淋巴细胞性白血病样本评估FDA批准的磷酸二酯酶4（PDE4）抑制剂roflumilast和idelalisib联合对细胞存活和肿瘤生长的影响。通过基因敲除或过表达研究BCR下游信号通路。研究结果表明，roflumilast会增加胞内cyclic-AMP水平，与idelalisib在抑制肿瘤生长和PI3K活性方面具有协同作用。进一步机制研究表明，roflumilast通过阻滞P85调节亚单位BCR介导活化来抑制PI3K，这一点与idelalisib不同，idelalisib是P110亚单位的ATP竞争性抑制剂。作者还通过基因研究将P85活化的PDE4调节性改变与致癌激酶SYK相联系。

文章最后认为，roflumilast和idelalisib抑制PI3K具有明确机制，解释了其协同作用的基础，治疗BCR依赖恶性肿瘤时需对PDE4抑制剂给予关注。

原始出处：
Jeffrey D.Cooney,An-Ping Lin,et al.Synergistic Targeting of the Regulatory and Catalytic Subunits of PI3Kδin Mature B-cell Malignancies.CLIN CANCER RES.March 2018 doi:10.1158/1078-0432.CCR-17-2218

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    2019-02-03 mhm289

    #PI3Kδ#

    0

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    2018-03-10 xiaoyeshuang

    #B细胞#

    0

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    2018-03-10 ms1292405679162969

    #PI3K#

    0

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    2018-03-10 chenzhuanggui

    #B细胞恶性肿瘤#

    0