Polo-like-kinase 1 (PLK-1) and c-myc inhibition with the dual kinase-bromodomain inhibitor volasertib in aggressive lymphomas.
Polo-like-kinase 1 (PLK-1) and c-myc inhibition with the dual kinase-bromodomain inhibitor volasertib in aggressive lymphomas.
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刺激性淋巴瘤中的双重激酶 - 溴结构域抑制剂伏拉替氏菌的polo样酶1（PLK-1）和C-MYC抑制作用。
DOI：
10.18632/oncotarget.22967
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发表时间：
2017-12-29
期刊：
影响因子：
--
通讯作者：
Wilcox RA
中科院分区：
文献类型：
--
作者：
Murga-Zamalloa C;Polk A;Hanel W;Chowdhury P;Brown N;Hristov AC;Bailey NG;Wang T;Phillips T;Devata S;Poonnen P;Gomez-Gelvez J;Inamdar KV;Wilcox RA
大多数患有 T 细胞淋巴增殖性疾病的患者在接受蒽环类化疗后的生存率仍然很差。这可能至少部分归因于在这些淋巴瘤中观察到的化疗耐药的细胞自主机制，包括重要肿瘤抑制因子的丧失和信号级联的激活，最终导致促进细胞生长和存活的转录因子的表达和激活。因此，需要确定新的治疗靶点。为了鉴定新的肿瘤依赖性，我们针对约 500 种激酶进行了功能丧失筛选，并鉴定了 polo 样激酶 1 (PLK-1)。这种激酶与包括 c-Myc 在内的重要癌基因的分子串扰有关，c-Myc 本身就是 T 细胞淋巴瘤亚型和高级别（“双重打击”）弥漫性大 B 细胞淋巴瘤的一个有吸引力的治疗靶点。我们证明 PLK-1 表达在这些侵袭性淋巴瘤中普遍存在，并且与 c-myc 表达相关。重要的是，用 PLK-1 抑制剂 volasertib 抑制 PLK-1 显着降低下游 c-myc 磷酸化，并削弱 BRD4 与 c-myc 基因的结合，从而抑制 c-myc 转录。因此，volasertib 导致细胞系和肿瘤异种移植物中 c-myc 表达几乎完全丧失，诱导细胞凋亡，因此值得对这些侵袭性淋巴瘤进行进一步研究。
Survival following anthracycline-based chemotherapy remains poor among patients with most T-cell lymphoproliferative disorders. This may be attributed, at least in part, to cell-autonomous mechanisms of chemotherapy resistance observed in these lymphomas, including the loss of important tumor suppressors and the activation of signaling cascades that culminate in the expression and activation of transcription factors promoting cell growth and survival. Therefore, the identification of novel therapeutic targets is needed. In an effort to identify novel tumor dependencies, we performed a loss-of-function screen targeting ≈500 kinases and identified polo-like kinase 1 (PLK-1). This kinase has been implicated in the molecular cross-talk with important oncogenes, including c-Myc, which is itself an attractive therapeutic target in subsets of T-cell lymphomas and in high-grade (“double hit”) diffuse large B-cell lymphomas. We demonstrate that PLK-1 expression is prevalent among these aggressive lymphomas and associated with c-myc expression. Importantly, PLK-1 inhibtion with the PLK-1 inhibitor volasertib significantly reduced downstream c-myc phosphorylation and impaired BRD4 binding to the c-myc gene, thus inhibiting c-myc transcription. Therefore, volasertib led to a nearly complete loss of c-myc expression in cell lines and tumor xenografts, induced apoptosis, and thus warrants further investigation in these aggressive lymphomas.
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