Synergistic effect of the γ-secretase inhibitor PF-03084014 and docetaxel in breast cancer models

Stem Cells Transl Med. 2013 Mar;2(3):233-42. doi: 10.5966/sctm.2012-0096. Epub 2013 Feb 13.

Abstract

Notch signaling mediates breast cancer cell survival and chemoresistance. In this report, we aimed to evaluate the antitumor efficacy of PF-03084014 in combination with docetaxel in triple-negative breast cancer models. The mechanism of action was investigated. PF-03084014 significantly enhanced the antitumor activity of docetaxel in multiple xenograft models including HCC1599, MDA-MB-231Luc, and AA1077. Docetaxel activated the Notch pathway by increasing the cleaved Notch1 intracellular domain and suppressing the endogenous Notch inhibitor NUMB. PF-03084014 used in combination with docetaxel reversed these effects and demonstrated early-stage synergistic apoptosis. Docetaxel elicited chemoresistance by elevating cytokine release and expression of survivin and induced an endothelial mesenchymal transition (EMT) phenotype by increasing the expressions of Snail, Slug, and N-cadherin. When reimplanted, the docetaxel-residual cells not only became much more tumorigenic, as evidenced by a higher fraction of tumor-initiating cells (TICs), but also showed higher metastatic potential compared with nontreated cells, leading to significantly shortened survival. In contrast, PF-03084014 was able to suppress expression of survivin and MCL1, reduce ABCB1 and ABCC2, upregulate BIM, reverse the EMT phenotype, and diminish the TICs. Additionally, the changes to the ALDH(+) and CD133(+)/CD44(+) subpopulations following therapy corresponded with the TIC self-renewal assay outcome. In summary, PF-03084014 demonstrated synergistic effects with docetaxel through multiple mechanisms. This work provides a strong preclinical rationale for the clinical utility of PF-03084014 to improve taxane therapy.

MeSH terms

  • AC133 Antigen
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Antigens, CD / metabolism
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cytokines / metabolism
  • Docetaxel
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Epithelial-Mesenchymal Transition / drug effects
  • Female
  • Glycoproteins / metabolism
  • Humans
  • Hyaluronan Receptors / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, SCID
  • Nerve Tissue Proteins / metabolism
  • Peptides / metabolism
  • Receptor, Notch1 / metabolism
  • Signal Transduction / drug effects
  • Taxoids / administration & dosage
  • Tetrahydronaphthalenes / administration & dosage
  • Time Factors
  • Valine / administration & dosage
  • Valine / analogs & derivatives
  • Xenograft Model Antitumor Assays

Substances

  • AC133 Antigen
  • Antigens, CD
  • Biomarkers, Tumor
  • CD44 protein, human
  • Cytokines
  • Glycoproteins
  • Hyaluronan Receptors
  • Membrane Proteins
  • NOTCH1 protein, human
  • Nerve Tissue Proteins
  • Numb protein, human
  • PROM1 protein, human
  • Peptides
  • Prom1 protein, mouse
  • Receptor, Notch1
  • Taxoids
  • Tetrahydronaphthalenes
  • Docetaxel
  • Amyloid Precursor Protein Secretases
  • Valine
  • nirogacestat