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

p.aythelady61 shared this article with you from Inoreader A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis and Metastasis in Aneuploid Cancers. Via Head and Neck Related Articles A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis and Metastasis in Aneuploid Cancers. Mol Cancer Ther. 2020 Dec 04;: Authors: 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 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 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 mur ine 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. PMID: 33277443 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.