1. A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis, and Metastasis in Aneuploid Cancers
- Author
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Masanori Kawakami, Adam Kittai, Sarah J. Freemantle, Xiaoshan Zhang, Jing Wang, Bingliang Fang, Xi Liu, Lisa Maria Mustachio, John V. Heymach, Jonathan M. Kurie, Alexey V. Danilov, Zibo Chen, Cheng Hsin Wei, Xiuxia Liu, Ethan Dmitrovsky, Yulong Chen, Liliya Tyutyunyk-Massey, and Jason Roszik
- Subjects
0301 basic medicine ,Cancer Research ,Carcinogenesis ,Mice, Nude ,Biology ,Transfection ,medicine.disease_cause ,Article ,Metastasis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,Lung cancer ,Mitosis ,Cell Proliferation ,Anaphase ,Cyclin-Dependent Kinase 2 ,Cyclin-dependent kinase 2 ,Cancer ,Aneuploidy ,medicine.disease ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,KRAS - Abstract
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 antineoplastic mechanism, induced anaphase catastrophe was explored in different aneuploid cancers after treatment with CYC065 (Cyclacel), a CDK2/9 inhibitor. Antineoplastic activity was studied in preclinical 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 antineoplastic mechanism. Reverse phase protein arrays (RPPAs) revealed that along with known CDK2/9 targets, focal adhesion kinase 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. Immunohistochemistry analysis of CYC065-treated lung cancer PDX models confirmed repression of proteins highlighted by RPPAs, implicating them as indicators of CYC065 antitumor 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.
- Published
- 2021
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