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

Masanori Kawakami, Lisa Maria Mustachio, Jaime Rodriguez-Canales, Barbara Mino, Jason Roszik, Pan Tong, Jing Wang, J. Jack Lee, Ja Hye Myung, John V. Heymach, Faye M. Johnson, Seungpyo Hong, Lin Zheng, Shanhu Hu, Pamela Andrea Villalobos, Carmen Behrens, Ignacio Wistuba, Sarah Freemantle, Xi Liu, Ethan Dmitrovsky

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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 μM, induced apoptosis up to 42.6% (SD = 5.5%, P < .001) at 2 μM, and caused G1 or G2/M arrest in lung cancer cells with minimal effects on control cells (growth inhibition at 1 μM: 10.6%, SD = 3.6%, P = .32; apoptosis at 2 μM: 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 μM). 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.

Original languageEnglish
JournalJournal of the National Cancer Institute
Volume109
Issue number6
DOIs
Publication statusPublished - 2017 Jun 1

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kawakami, M., Mustachio, L. M., Rodriguez-Canales, J., Mino, B., Roszik, J., Tong, P., Wang, J., Lee, J. J., Myung, J. H., Heymach, J. V., Johnson, F. M., Hong, S., Zheng, L., Hu, S., Villalobos, P. A., Behrens, C., Wistuba, I., Freemantle, S., Liu, X., & Dmitrovsky, E. (2017). Next-Generation CDK2/9 Inhibitors and Anaphase Catastrophe in Lung Cancer. Journal of the National Cancer Institute, 109(6). https://doi.org/10.1093/jnci/djw297