title: Next-Generation CDK2/9 Inhibitors and Anaphase Catastrophe in Lung Cancer.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  Next-generation CDK2/9 inhibition elicits marked antineoplastic effects in lung cancer via anaphase catastrophe and reduced PEA15 phosphorylation.
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawakami
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Lisa Maria
authors.initials: LM
authors.lastname: Mustachio
authors.affiliation: Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Rodriguez-Canales
authors.affiliation: Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mino
authors.affiliation: Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Roszik
authors.affiliation: Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Pan
authors.initials: P
authors.lastname: Tong
authors.affiliation: Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, The University of Illinois, Chicago, IL, USA.
authors.forename: Ja Hye
authors.initials: JH
authors.lastname: Myung
authors.affiliation: Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Faye M
authors.initials: FM
authors.lastname: Johnson
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, The University of Illinois, Chicago, IL, USA.
authors.forename: Seungpyo
authors.initials: S
authors.lastname: Hong
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: Shanhu
authors.initials: S
authors.lastname: Hu
authors.affiliation: Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Pamela Andrea
authors.initials: PA
authors.lastname: Villalobos
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.affiliation: Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Wistuba
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Freemantle
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Dmitrovsky
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000705:Anaphase / Q000187:drug effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018385:Centrosome / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; C000621592:CCT68127; C000621593:CYC065; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; C490444:Pea15 protein, mouse; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D051357:Cyclin-Dependent Kinase 2; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D000241:Adenosine