Next-Generation CDK2/9 Inhibitors and Anaphase Catastrophe in Lung Cancer.

ABSTRACT: Background:The first generation CDK2/7/9 inhibitor seliciclib (CYC202) causes multipolar anaphase and apoptosis in lung cancer cells with supernumerary centrosomes (known as anaphase catastrophe). We investigated a new and potent CDK2/9 inhibitor, CCT68127 (Cyclacel). Methods:CCT68127 was studied in lung cancer cells (three murine and five human) and control murine pulmonary epithelial and human immortalized bronchial epithelial cells. Robotic CCT68127 cell-based proliferation screens were used. Cells undergoing multipolar anaphase and inhibited centrosome clustering were scored. Reverse phase protein arrays (RPPAs) assessed CCT68127 effects on signaling pathways. The function of PEA15, a growth regulator highlighted by RPPAs, was analyzed. Syngeneic murine lung cancer xenografts (n?=?4/group) determined CCT68127 effects on tumorigenicity and circulating tumor cell levels. All statistical tests were two-sided. Results:CCT68127 inhibited growth up to 88.5% (SD?=?6.4%, P < .003) at 1??M, induced apoptosis up to 42.6% (SD?=?5.5%, P < .001) at 2??M, and caused G1 or G2/M arrest in lung cancer cells with minimal effects on control cells (growth inhibition at 1??M: 10.6%, SD?=?3.6%, P = .32; apoptosis at 2??M: 8.2%, SD?=?1.0%, P = .22). A robotic screen found that lung cancer cells with KRAS mutation were particularly sensitive to CCT68127 ( P = .02 for IC 50 ). CCT68127 inhibited supernumerary centrosome clustering and caused anaphase catastrophe by 14.1% (SD?=?3.6%, P < .009 at 1??M). CCT68127 reduced PEA15 phosphorylation by 70% (SD?=?3.0%, P = .003). The gain of PEA15 expression antagonized and its loss enhanced CCT68127-mediated growth inhibition. CCT68127 reduced lung cancer growth in vivo ( P < .001) and circulating tumor cells ( P = .004). Findings were confirmed with another CDK2/9 inhibitor, CYC065. Conclusions:Next-generation CDK2/9 inhibition elicits marked antineoplastic effects in lung cancer via anaphase catastrophe and reduced PEA15 phosphorylation.

SUBMITTER: Kawakami M 

PROVIDER: S-EPMC6059250 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature