Skip NavigationSkip to Content
Return Return to Search Results

Polo-like kinase 4 inhibition produces polyploidy and apoptotic death of lung cancers

  1. Author:
    Kawakami, Masanori
    Mustachio, Lisa Maria
    Zheng, Lin
    Chen, Yulong
    Rodriguez-Canales, Jaime
    Mino, Barbara
    Kurie, Jonathan M
    Roszik, Jason
    Villalobos, Pamela Andrea
    Thu, Kelsie L
    Silvester, Jennifer
    Cescon, David W
    Wistuba, Ignacio I
    Mak, Tak W
    Liu, Xi
    Dmitrovsky, Ethan

  2. Author Address

    Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada., Department of Medicine, University of Toronto, Toronto, ON M5G 1L7, Canada., The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Tak.Mak@uhnresearch.ca., Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada., Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21701.,
    1. Year: 2018
    2. Date: Feb 20
    3. Epub Date: 2018 02 06
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 115
    2. 8
    3. Pages: 1913-1918
  4. Type of Article: Article
  1. Abstract:

    Polo-like kinase 4 (PLK4) is a serine/threonine kinase regulating centriole duplication. CFI-400945 is a highly selective PLK4 inhibitor that deregulates centriole duplication, causing mitotic defects and death of aneuploid cancers. Prior work was substantially extended by showing CFI-400945 causes polyploidy, growth inhibition, and apoptotic death of murine and human lung cancer cells, despite expression of mutatedKRASor p53. Analysis of DNA content by propidium iodide (PI) staining revealed cells with >4N DNA content (polyploidy) markedly increased after CFI-400945 treatment. Centrosome numbers and mitotic spindles were scored. CFI-400945 treatment produced supernumerary centrosomes and mitotic defects in lung cancer cells. In vivo antineoplastic activity of CFI-400945 was established in mice with syngeneic lung cancer xenografts. Lung tumor growth was significantly inhibited at well-tolerated dosages. Phosphohistone H3 staining of resected lung cancers following CFI-400945 treatment confirmed the presence of aberrant mitosis. PLK4 expression profiles in human lung cancers were explored using The Cancer Genome Atlas (TCGA) and RNA in situ hybridization (RNA ISH) of microarrays containing normal and malignant lung tissues. PLK4 expression was significantly higher in the malignant versus normal lung and conferred an unfavorable survival (P< 0.05). Intriguingly, cyclin dependent kinase 2 (CDK2) antagonism cooperated with PLK4 inhibition. Taken together, PLK4 inhibition alone or as part of a combination regimen is a promising way to combat lung cancer.

    See More

  1. Keywords:

External Sources

  1. View Full Text
  2. DOI: 10.1073/pnas.1719760115
  3. PMID: 29434041
  4. View record in Web of Science®
  5. WOS: 000425495000075
  6. PII : 1719760115

Library Notes

  1. Fiscal Year: FY2017-2018
NCI at Frederick

You are leaving a government website.

This external link provides additional information that is consistent with the intended purpose of this site. The government cannot attest to the accuracy of a non-federal site.

Linking to a non-federal site does not constitute an endorsement by this institution or any of its employees of the sponsors or the information and products presented on the site. You will be subject to the destination site's privacy policy when you follow the link.

ContinueCancel