A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis, and Metastasis in Aneuploid Cancers.
A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis, and Metastasis in Aneuploid Cancers.
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一种新型CDK 2/9抑制剂CYC 065导致非整倍体癌症的后期灾难并抑制增殖、肿瘤发生和转移
DOI：
10.1158/1535-7163.mct-19-0987
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发表时间：
2021-03
影响因子：
5.7
通讯作者：
Dmitrovsky E
中科院分区：
文献类型：
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作者：
Kawakami M;Mustachio LM;Chen Y;Chen Z;Liu X;Wei CH;Roszik J;Kittai AS;Danilov AV;Zhang X;Fang B;Wang J;Heymach JV;Tyutyunyk-Massey L;Freemantle SJ;Kurie JM;Liu X;Dmitrovsky E
细胞周期蛋白依赖性激酶2(CDK2)拮抗剂抑制有丝分裂时过多的中心体聚集，导致多极细胞分裂和细胞凋亡性死亡。这被称为后期灾难。为了建立诱导后期突变作为一种临床上易于处理的抗肿瘤机制，对不同非整倍体肿瘤用CDK2/9抑制剂Cyclacel处理后的诱导后期突变进行了研究。抗肿瘤活性在临床前模型中进行了研究。尽管KRAS癌蛋白表达，但CYC065治疗增加了包括淋巴瘤、肺癌、结肠癌和胰腺癌在内的各种癌症的后期灾难。后期巨灾是一种广泛活跃的抗肿瘤机制。逆相蛋白质阵列(RPPA)显示，与已知的CDK2/9靶点一样，调节转移的粘着斑激酶(FAK)和Src磷酸化都被CyC065处理抑制。耐人寻味的是，在活体小鼠模型中，CYC065治疗降低了肺癌转移。CYC065治疗还显著降低了同基因小鼠和患者来源的异种移植(PDX)模型中肺癌的生长速度，而不依赖于KRAS癌蛋白的表达。对经CYC065治疗的肺癌PDX模型的免疫组织化学分析证实，RPPAs突出显示的蛋白质受到抑制，暗示它们是CYC065抗肿瘤反应的指示物。磷酸组蛋白H3染色检测到细胞周期蛋白065处理后的PDX细胞发生了后期突变。因此，尽管KRAS癌蛋白表达，但CyC065治疗后诱导的后期灾难可以对抗非整倍体癌症。这些发现应该会指导这种新型的CDK2/9抑制剂在癌症临床上的未来试验。
Cyclin dependent kinase 2 (CDK2) antagonism inhibits clustering of excessive centrosomes at mitosis, causing multipolar cell division and apoptotic death. This is called anaphase catastrophe. To establish induced anaphase catastrophe as a clinically-tractable anti-neoplastic mechanism, induced anaphase catastrophe was explored in different aneuploid cancers after treatment with CYC065 (Cyclacel), a CDK2/9 inhibitor. Anti-neoplastic activity was studied in pre-clinical models. CYC065-treatment augmented anaphase catastrophe in diverse cancers including lymphoma, lung, colon and pancreatic cancers, despite KRAS oncoprotein expression. Anaphase catastrophe was a broadly active anti-neoplastic mechanism. Reverse phase protein arrays (RPPAs) revealed that along with known CDK2/9 targets, focal adhesion kinase (FAK) and Src phosphorylation that regulate metastasis were each repressed by CYC065-treatment. Intriguingly, CYC065-treatment decreased lung cancer metastases in in vivo murine models. CYC065-treatment also significantly reduced the rate of lung cancer growth in syngeneic murine and patient-derived xenograft (PDX) models independent of KRAS oncoprotein expression. Immunohistochemical analysis of CYC065-treated lung cancer PDX models confirmed repression of proteins highlighted by RPPAs, implicating them as indicators of CYC065 anti-tumor response. Phospho-histone H3 staining detected anaphase catastrophe in CYC065-treated PDXs. Thus, induced anaphase catastrophe after CYC065-treatment can combat aneuploid cancers despite KRAS oncoprotein expression. These findings should guide future trials of this novel CDK2/9 inhibitor in the cancer clinic.