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

doi:10.1093/jnci/djw297

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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39 Scopus citations

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 lM, induced apoptosis up to 42.6% (SD = 5.5%, P < .001) at 2 lM, and caused G1 or G2/M arrest in lung cancer cells with minimal effects on control cells (growth inhibition at 1 lM: 10.6%, SD = 3.6%, P = .32; apoptosis at 2 lM: 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 IC₅₀). CCT68127 inhibited supernumerary centrosome clustering and caused anaphase catastrophe by 14.1% (SD = 3.6%, P < .009 at 1 lM). 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 language	English (US)
Article number	djw297
Journal	Journal of the National Cancer Institute
Volume	109
Issue number	6
DOIs	https://doi.org/10.1093/jnci/djw297
State	Published - Jun 1 2017

ASJC Scopus subject areas

Oncology
Cancer Research

MD Anderson CCSG core facilities

Bioinformatics Shared Resource
Biostatistics Resource Group
Research Animal Support Facility
Small Animal Imaging Facility

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10.1093/jnci/djw297

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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), Article djw297. https://doi.org/10.1093/jnci/djw297

Kawakami, M, Mustachio, LM, Rodriguez-Canales, J, Mino, B, Roszik, J, Tong, P, Wang, J , Lee, JJ, Myung, JH, Heymach, JV , Johnson, FM, Hong, S, Zheng, L, Hu, S, Villalobos, PA, 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, vol. 109, no. 6, djw297. https://doi.org/10.1093/jnci/djw297

@article{b36332f9af5a45259da2370502c1afe5,

title = "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 lM, induced apoptosis up to 42.6% (SD = 5.5%, P < .001) at 2 lM, and caused G1 or G2/M arrest in lung cancer cells with minimal effects on control cells (growth inhibition at 1 lM: 10.6%, SD = 3.6%, P = .32; apoptosis at 2 lM: 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 IC50). CCT68127 inhibited supernumerary centrosome clustering and caused anaphase catastrophe by 14.1% (SD = 3.6%, P < .009 at 1 lM). 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.",

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

year = "2017",

month = jun,

day = "1",

doi = "10.1093/jnci/djw297",

language = "English (US)",

volume = "109",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "6",

}

TY - JOUR

T1 - Next-Generation CDK2/9 Inhibitors and Anaphase Catastrophe in Lung Cancer

AU - Kawakami, Masanori

AU - Mustachio, Lisa Maria

AU - Rodriguez-Canales, Jaime

AU - Mino, Barbara

AU - Roszik, Jason

AU - Tong, Pan

AU - Wang, Jing

AU - Lee, J. Jack

AU - Myung, Ja Hye

AU - Heymach, John V.

AU - Johnson, Faye M.

AU - Hong, Seungpyo

AU - Zheng, Lin

AU - Hu, Shanhu

AU - Villalobos, Pamela Andrea

AU - Behrens, Carmen

AU - Wistuba, Ignacio

AU - Freemantle, Sarah

AU - Liu, Xi

AU - Dmitrovsky, Ethan

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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 lM, induced apoptosis up to 42.6% (SD = 5.5%, P < .001) at 2 lM, and caused G1 or G2/M arrest in lung cancer cells with minimal effects on control cells (growth inhibition at 1 lM: 10.6%, SD = 3.6%, P = .32; apoptosis at 2 lM: 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 IC50). CCT68127 inhibited supernumerary centrosome clustering and caused anaphase catastrophe by 14.1% (SD = 3.6%, P < .009 at 1 lM). 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.

AB - 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 lM, induced apoptosis up to 42.6% (SD = 5.5%, P < .001) at 2 lM, and caused G1 or G2/M arrest in lung cancer cells with minimal effects on control cells (growth inhibition at 1 lM: 10.6%, SD = 3.6%, P = .32; apoptosis at 2 lM: 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 IC50). CCT68127 inhibited supernumerary centrosome clustering and caused anaphase catastrophe by 14.1% (SD = 3.6%, P < .009 at 1 lM). 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.

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DO - 10.1093/jnci/djw297

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AN - SCOPUS:85027275593

SN - 0027-8874

VL - 109

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 6

M1 - djw297

ER -

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

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MD Anderson CCSG core facilities

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