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.

Epithelial-mesenchymal transition and drug resistance in breast cancer (Review)

“…Genomic Region Enrichment was performed to find increased secretase activity which may account for an increased Notch signaling in endocrine resistant breast cancer cells (50). pF-03084014 which inhibits Notch signaling by reducing Notch intracellular domain (NICD) and Notch target genes Hes-1 and c-Myc in both cells and tumors prominently enhanced the antitumor activity of docetaxel in MDA-Mb-231 xenograft model through suppressing expression of survivin and myeloid cell leukemia sequence 1 (MCL1), reducing ABCB1 and ABCC2, upregulating BIM and reversing the EMT phenotype (51). Notch may be an important target in trastuzumab-resistant, HER-2 + breast cancer.…”

A Phase I, Dose-Finding Study in Patients with Advanced Solid Malignancies of the Oral γ-Secretase Inhibitor PF-03084014

“…PF-03084014 is a selective, noncompetitive, reversible inhibitor of g-secretase that has demonstrated substantial antitumor activity in multiple, NOTCH-dependent, preclinical models at well-tolerated doses (17)(18)(19)(20). Single-and multiple-dose administration of PF-03084014 was deemed to be safe and well tolerated at the tested dose levels, based on the results of phase I studies conducted in healthy volunteers.…”

Prognostic significance of ABCB1 in stage I lung adenocarcinoma

“…CSCs exhibit similar properties to those of normal stem cells, suggesting that these signaling pathways are important in maintaining CSCs in a variety of cancers, including lung (5,27). Previous studies reported that ABCB1 expression was affected by the above signaling pathways (28)(29)(30). However, the association between ABCB1 and these signaling pathways should be further confirmed in NSCLC patients.…”