Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers
Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers
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DOI：
10.1158/1535-7163.mct-16-0390
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发表时间：
2017-02-01
影响因子：
5.7
通讯作者：
Wang, Jing
中科院分区：
文献类型：
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作者：
Sun, Kaiming;Atoyan, Ruzanna;Wang, Jing
MYC的上调是人类癌症中常见的驱动事件，并且一些肿瘤依赖于MYC来维持促进细胞生长和增殖的转录程序。临床前研究表明，单独靶向MYC的上游调节因子，如组蛋白脱乙酰酶（HDAC）和磷酸肌醇3-激酶（PI 3 K），可以降低MYC蛋白水平并抑制MYC驱动的癌症的生长。HDAC和PI 3 K抑制在诱导癌细胞死亡中的协同作用也有报道，但MYC调节的参与尚不清楚。在这项研究中，我们证明了HDAC和PI 3 K抑制协同下调MYC蛋白水平，并诱导“双重打击”（DH）弥漫性大B细胞淋巴瘤（DLBCL）细胞的凋亡。此外，CUDC-907（I类和II类HDAC和I类PI 3 K的小分子双重作用抑制剂）有效地抑制MYC改变的或MYC依赖性癌细胞（例如DH DLBCL和BRDNUT融合阳性NUT中线癌（NMC）细胞）的生长和存活，并且MYC蛋白下调是由CUDC-907治疗诱导的早期事件。一致地，CUDC-907针对多种MYC驱动的癌症类型的抗肿瘤活性也在动物模型中得到证实，包括DLBCL和NMC异种移植物模型、Myc转基因肿瘤同基因模型和MYC扩增的实体瘤患者来源的异种移植物（PDX）模型。我们的研究结果表明，双功能HDAC和PI 3 K抑制剂CUDC-907是一种有效的药物靶向MYC，因此可能被开发为MYC依赖性癌症的潜在治疗。
Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDAC) and phosphoinositide 3-kinases (PI3K), can reduce MYC protein levels and suppress the growth of MYCdriven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear. In this study, we demonstrated that HDAC and PI3K inhibition synergistically downregulates MYC protein levels and induces apoptosis in "double-hit" (DH) diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, CUDC-907, a small-molecule dual-acting inhibitor of both class I and II HDACs and class I PI3Ks, effectively suppresses the growth and survival of MYC-altered or MYC-dependent cancer cells, such as DH DLBCL and BRDNUT fusion-positive NUT midline carcinoma (NMC) cells, and MYC protein downregulation is an early event induced by CUDC-907 treatment. Consistently, the antitumor activity of CUDC-907 against multiple MYC-driven cancer types was also demonstrated in animal models, including DLBCL and NMC xenograft models, Myc transgenic tumor syngeneic models, and MYC-amplified solid tumor patient-derived xenograft (PDX) models. Our findings suggest that dual function HDAC and PI3K inhibitor CUDC-907 is an effective agent targeting MYC and thus may be developed as potential therapy for MYCdependent cancers.