title: CDK2 Inhibition Causes Anaphase Catastrophe in Lung Cancer through the Centrosomal Protein CP110.
abstract: Aneuploidy is frequently detected in human cancers and is implicated in carcinogenesis. Pharmacologic targeting of aneuploidy is an attractive therapeutic strategy, as this would preferentially eliminate malignant over normal cells. We previously discovered that CDK2 inhibition causes lung cancer cells with more than two centrosomes to undergo multipolar cell division leading to apoptosis, defined as anaphase catastrophe. Cells with activating KRAS mutations were especially sensitive to CDK2 inhibition. Mechanisms of CDK2-mediated anaphase catastrophe and how activated KRAS enhances this effect were investigated. Live-cell imaging provided direct evidence that following CDK2 inhibition, lung cancer cells develop multipolar anaphase and undergo multipolar cell division with the resulting progeny apoptotic. The siRNA-mediated repression of the CDK2 target and centrosome protein CP110 induced anaphase catastrophe of lung cancer cells. In contrast, CP110 overexpression antagonized CDK2 inhibitor-mediated anaphase catastrophe. Furthermore, activated KRAS mutations sensitized lung cancer cells to CDK2 inhibition by deregulating CP110 expression. Thus, CP110 is a critical mediator of CDK2 inhibition-driven anaphase catastrophe. Independent examination of murine and human paired normal-malignant lung tissues revealed marked upregulation of CP110 in malignant versus normal lung. Human lung cancers with KRAS mutations had significantly lower CP110 expression as compared with KRAS wild-type cancers. Thus, a direct link was found between CP110 and CDK2 inhibitor antineoplastic response. CP110 plays a mechanistic role in response of lung cancer cells to CDK2 inhibition, especially in the presence of activated KRAS mutations.
authors: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: Shanhu
authors: S
authors: Hu
authors: Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. The Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: Alexey V
authors: AV
authors: Danilov
authors: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. The Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: Kristina
authors: K
authors: Godek
authors: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. The Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: Bernardo
authors: B
authors: Orr
authors: Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors: Laura J
authors: LJ
authors: Tafe
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Jaime
authors: J
authors: Rodriguez-Canales
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Carmen
authors: C
authors: Behrens
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Barbara
authors: B
authors: Mino
authors: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Cesar A
authors: CA
authors: Moran
authors: The Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors: Vincent A
authors: VA
authors: Memoli
authors: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: Lisa Maria
authors: LM
authors: Mustachio
authors: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: Fabrizio
authors: F
authors: Galimberti
authors: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: Saranya
authors: S
authors: Ravi
authors: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: Andrew
authors: A
authors: DeCastro
authors: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: Yun
authors: Y
authors: Lu
authors: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: David
authors: D
authors: Sekula
authors: The Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors: Angeline S
authors: AS
authors: Andrew
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Ignacio I
authors: II
authors: Wistuba
authors: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: Sarah
authors: S
authors: Freemantle
authors: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. The Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: Duane A
authors: DA
authors: Compton
authors: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. The Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. ethan.dmitrovsky@dartmouth.edu.
authors: Ethan
authors: E
authors: Dmitrovsky
mesh_terms: D000705:Anaphase / Q000187:drug effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C467559:CCP110 protein, human; D018797:Cell Cycle Proteins; C117307:KRAS protein, human; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D011687:Purines; D000077546:Roscovitine; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins