title: 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: Pfizer Global Research and Development, La Jolla, CA, USA. cathy.zhang@pfizer.com
authors: Cathy C
authors: CC
authors: Zhang
authors: Zhengming
authors: Z
authors: Yan
authors: Qing
authors: Q
authors: Zong
authors: Douglas D
authors: DD
authors: Fang
authors: Cory
authors: C
authors: Painter
authors: Qin
authors: Q
authors: Zhang
authors: Enhong
authors: E
authors: Chen
authors: Maruja E
authors: ME
authors: Lira
authors: Annette
authors: A
authors: John-Baptiste
authors: James G
authors: JG
authors: Christensen
mesh_terms: D000071916:AC133 Antigen; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D000089762:Multidrug Resistance-Associated Protein 2; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000008:administration & dosage; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage; D013997:Time Factors; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives; D023041:Xenograft Model Antitumor Assays
chemical_list: C000715087:ABCC2 protein, human; D000071916:AC133 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D016207:Cytokines; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D008565:Membrane Proteins; D000089762:Multidrug Resistance-Associated Protein 2; C497761:NOTCH1 protein, human; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D051881:Receptor, Notch1; D043823:Taxoids; D013764:Tetrahydronaphthalenes; D000077143:Docetaxel; D053829:Amyloid Precursor Protein Secretases; D014633:Valine; C550722:nirogacestat