PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer

Nat Med. 2016 Nov;22(11):1303-1313. doi: 10.1038/nm.4198. Epub 2016 Oct 24.

Abstract

Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC cells, but not nonmalignant mammary epithelial cells, were dependent on PIM1 for proliferation and protection from apoptosis. PIM1 knockdown reduced expression of the anti-apoptotic factor BCL2, and dynamic BH3 profiling of apoptotic priming revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines. In TNBC tumors and their cellular models, PIM1 expression was associated with several transcriptional signatures involving the transcription factor MYC, and PIM1 depletion in TNBC cell lines decreased, in a MYC-dependent manner, cell population growth and expression of the MYC target gene MCL1. Treatment with the pan-PIM kinase inhibitor AZD1208 impaired the growth of both cell line and patient-derived xenografts and sensitized them to standard-of-care chemotherapy. This work identifies PIM1 as a malignant-cell-selective target in TNBC and the potential use of PIM1 inhibitors for sensitizing TNBC to chemotherapy-induced apoptotic cell death.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Biphenyl Compounds / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics*
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • DNA Copy Number Variations
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Humans
  • Mice
  • Mitochondria / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Neoplasm Transplantation
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-pim-1 / genetics*
  • Real-Time Polymerase Chain Reaction
  • Thiazolidines / pharmacology
  • Triple Negative Breast Neoplasms / genetics*
  • Xenograft Model Antitumor Assays

Substances

  • AZD1208
  • BCL2 protein, human
  • Biphenyl Compounds
  • MCL1 protein, human
  • MYC protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-myc
  • Thiazolidines
  • PIM1 protein, human
  • Proto-Oncogene Proteins c-pim-1