“Synergistic Effect of the γ-Secretase Inhibitor PF-03084014 and Docetaxel in Breast Cancer Models”
From Stem Cells Translational Medicine
Notch signaling, which plays a role in a variety of developmental processes by controlling cell fate decisions through the regulation of interactions between physically adjacent cells, has also been linked to tumourigenesis, especially breast cancer (Ranganathan et al). Activation of this pathway leads to the γ-secretase-mediated cleavage of Notch and the release of the Notch intracellular domain (NICD), which translocates to the nucleus and activates a cascade of transcriptional events that mediate cellular proliferation, differentiation, and apoptosis. With regards to breast cancer, elevated levels of Notch signalling have been observed in breast cancer tumour-initiating cells (TICs) compared with bulk tumour cells (Grudzien et al, Farnie and Clarke and Wright et al) suggesting that Notch may be an effective target for anti-tumourigenic therapies. Indeed previous efforts to inhibit Notch signalling, by the blockade of Notch ligands Dll4 (Hoey et al) and the γ-secretase inhibitor (GSI) (Grudzien et al and Kondratyev et al], reduced TIC numbers, while the γ-secretase inhibitor PF-03084014 has been shown to be effective in haematological and breast xenograft models (Wei et al and Zhang et al). Now, researchers from the group of James G. Christensen at the Oncology Research Unit, Pfizer Global Research and Development, San Diego, USA have studied the synergistic effects of PF-03084014 with docetaxel, a common chemotherapeutic, in triple-negative breast cancer, finding that PF-03084014 significantly enhanced the antitumor activity of docetaxel and report on the mechanisms behind this effect (Zhang et al).