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Molecular Cancer Therapeutics
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Small Molecule Therapeutics

A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis, and Metastasis in Aneuploid Cancers

Masanori Kawakami, Lisa Maria Mustachio, Yulong Chen, Zibo Chen, Xiuxia Liu, Cheng-Hsin Wei, Jason Roszik, Adam S. Kittai, Alexey V. Danilov, Xiaoshan Zhang, Bingliang Fang, Jing Wang, John V. Heymach, Liliya Tyutyunyk-Massey, Sarah J. Freemantle, Jonathan M. Kurie, Xi Liu and Ethan Dmitrovsky
Masanori Kawakami
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Frederick National Laboratory for Cancer Research, Frederick, Maryland.
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Lisa Maria Mustachio
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Yulong Chen
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Zibo Chen
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Frederick National Laboratory for Cancer Research, Frederick, Maryland.
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Xiuxia Liu
2Frederick National Laboratory for Cancer Research, Frederick, Maryland.
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Cheng-Hsin Wei
2Frederick National Laboratory for Cancer Research, Frederick, Maryland.
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Jason Roszik
3Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Adam S. Kittai
5Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
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Alexey V. Danilov
5Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
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Xiaoshan Zhang
6Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Bingliang Fang
6Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • ORCID record for Bingliang Fang
Jing Wang
7Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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John V. Heymach
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Liliya Tyutyunyk-Massey
2Frederick National Laboratory for Cancer Research, Frederick, Maryland.
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Sarah J. Freemantle
8University of Illinois, Urbana, Illinois.
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Jonathan M. Kurie
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Xi Liu
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Frederick National Laboratory for Cancer Research, Frederick, Maryland.
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Ethan Dmitrovsky
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Frederick National Laboratory for Cancer Research, Frederick, Maryland.
9Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: ethan.dmitrovsky@nih.gov
DOI: 10.1158/1535-7163.MCT-19-0987 Published March 2021
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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.

This article is featured in Highlights of This Issue, p. 453

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2021;20:477–89

  • Received October 16, 2019.
  • Revision received June 18, 2020.
  • Accepted November 30, 2020.
  • Published first December 4, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 20 (3)
March 2021
Volume 20, Issue 3
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A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis, and Metastasis in Aneuploid Cancers
Masanori Kawakami, Lisa Maria Mustachio, Yulong Chen, Zibo Chen, Xiuxia Liu, Cheng-Hsin Wei, Jason Roszik, Adam S. Kittai, Alexey V. Danilov, Xiaoshan Zhang, Bingliang Fang, Jing Wang, John V. Heymach, Liliya Tyutyunyk-Massey, Sarah J. Freemantle, Jonathan M. Kurie, Xi Liu and Ethan Dmitrovsky
Mol Cancer Ther March 1 2021 (20) (3) 477-489; DOI: 10.1158/1535-7163.MCT-19-0987

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A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis, and Metastasis in Aneuploid Cancers
Masanori Kawakami, Lisa Maria Mustachio, Yulong Chen, Zibo Chen, Xiuxia Liu, Cheng-Hsin Wei, Jason Roszik, Adam S. Kittai, Alexey V. Danilov, Xiaoshan Zhang, Bingliang Fang, Jing Wang, John V. Heymach, Liliya Tyutyunyk-Massey, Sarah J. Freemantle, Jonathan M. Kurie, Xi Liu and Ethan Dmitrovsky
Mol Cancer Ther March 1 2021 (20) (3) 477-489; DOI: 10.1158/1535-7163.MCT-19-0987
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