TY - JOUR
T1 - A novel CDK2/9 inhibitor CYC065 causes anaphase catastrophe and represses proliferation, tumorigenesis, and metastasis in aneuploid cancers
AU - Kawakami, Masanori
AU - Mustachio, Lisa Maria
AU - Chen, Yulong
AU - Chen, Zibo
AU - Liu, Xiuxia
AU - Wei, Cheng Hsin
AU - Roszik, Jason
AU - Kittai, Adam S.
AU - Danilov, Alexey V.
AU - Zhang, Xiaoshan
AU - Fang, Bingliang
AU - Wang, Jing
AU - Heymach, John V.
AU - Tyutyunyk-Massey, Liliya
AU - Freemantle, Sarah J.
AU - Kurie, Jonathan M.
AU - Liu, Xi
AU - Dmitrovsky, Ethan
N1 - Funding Information:
This work was supported partly by the NIH, NCI grant R01-CA190722 (to X. Liu, S.J. Freemantle, and J.M. Kurie), a Samuel Waxman Cancer Research Foundation Award (ED), University of Texas Science and Technology Acquisition and Retention Award (E. Dmitrovsky), and from the NCI Intramural Research Program and Center for Cancer Research under NIH contracts HHSN26120080000IE and 75N91019D00024 (E. Dmitrovsky). PDX generation and annotation were supported by the University of Texas MD Anderson Cancer Center Moon Shots Program, Specialized Program of Research Excellence (SPORE) grant CA070907, and University of Texas PDX Development and Trial Center grant U54CA224065.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-19-0987
DO - 10.1158/1535-7163.MCT-19-0987
M3 - Article
C2 - 33277443
AN - SCOPUS:85102318833
SN - 1535-7163
VL - 20
SP - 477
EP - 489
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 3
ER -