Inhibition of Polo-like kinase 1 prevents the growth of metastatic breast cancer cells in the brain

Clin Exp Metastasis. 2011 Dec;28(8):899-908. doi: 10.1007/s10585-011-9421-9. Epub 2011 Sep 21.

Abstract

Few therapeutic strategies exist for the treatment of metastatic tumor cells in the brain because the blood-brain barrier (BBB) limits drug access. Thus the identification of molecular targets and accompanying BBB permeable drugs will significantly benefit brain metastasis patients. Polo-like kinase 1 (Plk1) is an attractive molecular target because it is only expressed in dividing cells and its expression is upregulated in many tumors. Analysis of a publicly available database of human breast cancer metastases revealed Plk1 mRNA expression was significantly increased in brain metastases compared to systemic metastases (P = 0.0018). The selective Plk1 inhibitor, GSK461364A, showed substantial uptake in normal rodent brain. Using a breast cancer brain metastatic xenograft model (231-BR), we tested the efficacy of GSK461364A to prevent brain metastatic colonization. When treatment was started 3 days post-injection, GSK461364A at 50 mg/kg inhibited the development of large brain metastases 62% (P = 0.0001) and prolonged survival by 17%. GSK461364A sensitized tumor cells to radiation induced cell death in vitro. Previously, it was reported that mutations in p53 might render tumor cells more sensitive to Plk1 inhibition; however, p53 mutations are uncommon in breast cancer. In a cohort of 41 primary breast tumors and matched brain metastases, p53 immunostaining was increased in 61% of metastases; 44% of which were associated with primary tumors with low p53. The data suggest that p53 overexpression occurs frequently in brain metastases and may facilitate sensitivity to Plk1 inhibition. These data indicate Plk1 may be a new druggable target for the prevention of breast cancer brain metastases.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / prevention & control
  • Bone Neoplasms / secondary
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / prevention & control*
  • Brain Neoplasms / secondary
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Breast Neoplasms / prevention & control*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Proliferation / drug effects
  • Female
  • Humans
  • Immunoenzyme Techniques
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Mice
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Radiation, Ionizing
  • Survival Rate
  • Thiophenes / pharmacology
  • Tissue Array Analysis
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53
  • Xenograft Model Antitumor Assays

Substances

  • Cell Cycle Proteins
  • GSK 461364A
  • Proto-Oncogene Proteins
  • TP53 protein, human
  • Thiophenes
  • Tumor Suppressor Protein p53
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1