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

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.

• Authors: Cathy C Zhang, Zhengming Yan, Qing Zong, Douglas D Fang, Cory Painter, Qin Zhang, Enhong Chen, Maruja E Lira, Annette John-Baptiste, James G Christensen
• Journal: Stem cells translational medicine (Stem Cells Transl Med) Vol. 2 Issue 3 Pg. 233-42 (Mar 2013) ISSN: 2157-6564 [Print] England
• PMID: 23408105 (Publication Type: Journal Article)

Chemical References

• ABCC2 protein, human
• AC133 Antigen
• Antigens, CD
• Biomarkers, Tumor
• CD44 protein, human
• Cytokines
• Glycoproteins
• Hyaluronan Receptors
• Membrane Proteins
• Multidrug Resistance-Associated Protein 2
• 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

Topics

• AC133 Antigen
• Amyloid Precursor Protein Secretases (antagonists & inhibitors, metabolism)
• Animals
• Antigens, CD (metabolism)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (drug therapy, enzymology, 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
• Multidrug Resistance-Associated Protein 2
• Nerve Tissue Proteins (metabolism)
• Peptides (metabolism)
• Receptor, Notch1 (metabolism)
• Signal Transduction (drug effects)
• Taxoids (administration & dosage)
• Tetrahydronaphthalenes (administration & dosage)
• Time Factors
• Valine (administration & dosage, analogs & derivatives)
• Xenograft Model Antitumor Assays