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.