Synergistic Targeting of the Regulatory and Catalytic Subunits of PI3Kδ in Mature B-cell Malignancies.
Synergistic Targeting of the Regulatory and Catalytic Subunits of PI3Kδ in Mature B-cell Malignancies.
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DOI：
10.1158/1078-0432.ccr-17-2218
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发表时间：
2018-03-01
期刊：
影响因子：
--
通讯作者：
Aguiar RCT
中科院分区：
文献类型：
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作者：
Cooney JD;Lin AP;Jiang D;Wang L;Suhasini AN;Myers J;Qiu Z;Wölfler A;Sill H;Aguiar RCT
B细胞受体（BCR）的异常激活与成熟B细胞肿瘤的发病机制有关，这一概念部分通过BCR相关激酶BTK（布鲁顿酪氨酸激酶）和PI 3 K δ（磷脂酰肌醇-4，5-二磷酸3-激酶δ）抑制剂的临床成功得到验证。这些抑制剂具有局限性，包括缺乏完全反应、获得性耐药性和毒性。在这里，我们研究了环AMP/PDE 4信号轴抑制PI 3 K的机制，以确定一种新的基于机制的组合策略来攻击成熟B细胞恶性肿瘤中的BCR依赖性。我们使用体外和体内弥漫性大B细胞淋巴瘤（DLBCL）细胞系和原发性慢性淋巴细胞白血病（CLL）样本，以临床前评估FDA批准的磷酸二酯酶4（PDE 4）抑制剂罗氟司特和艾代拉里斯对细胞存活和肿瘤生长的影响。采用功能获得和丧失的遗传模型来绘制BCR下游的多个信号中介。罗氟司特提高细胞内环AMP水平，并与艾代拉里斯协同抑制肿瘤生长和PI 3 K活性。从机制上讲，我们表明罗氟司特通过抑制BCR介导的P85调节亚基的活化来抑制PI 3 K，将其与催化P110亚基的ATP竞争性抑制剂idelalisib区分开来。使用遗传模型，我们将PDE 4调节的P85激活调节与致癌激酶SYK联系起来。这些数据表明，罗氟司特和艾代拉里斯通过不同的机制抑制PI 3 K，解释了它们协同作用的基础，并表明有必要重新利用PDE 4抑制剂来治疗BCR依赖性恶性肿瘤。
Aberrant activation of the B cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton’s tyrosine kinase) and PI3Kδ (Phosphatidylinositol-4,5-bisphosphate 3-kinase delta). These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, towards identifying a novel mechanism-based combinatorial strategy to attack BCR-dependency in mature B-cell malignancies. We used in vitro and in vivo diffuse large B-cell lymphoma (DLBCL) cell lines and primary chronic lymphocytic leukemia (CLL) samples to pre-clinically evaluate the effects of the combination of the FDA-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast and idelalisib on cell survival and tumor growth. Genetic models of gain- and loss-of-function were employed to map multiple signaling intermediaries downstream of the BCR. Roflumilast elevates the intracellular levels of cyclic-AMP and synergizes with idelalisib in suppressing tumor growth and PI3K activity. Mechanistically, we show that roflumilast suppresses PI3K by inhibiting BCR-mediated activation of the P85 regulatory subunit, distinguishing itself from idelalisib, an ATP-competitive inhibitor of the catalytic P110 subunit. Using genetic models, we linked the PDE4-regulated modulation of P85 activation to the oncogenic kinase SYK. These data demonstrate that roflumilast and idelalisib suppress PI3K by distinct mechanisms, explaining the basis for their synergism, and suggest that the repurposing of PDE4 inhibitors to treat BCR-dependent malignancies is warranted.