Synergistic antitumor effect of a γ-secretase inhibitor PF-03084014 and sorafenib in hepatocellular carcinoma.

Synergistic antitumor effect of a γ-secretase inhibitor PF-03084014 and sorafenib in hepatocellular carcinoma. Oncotarget. 2018 Oct 09;9(79):34996-35007 Authors: Yang X, Xia W, Chen L, Wu CX, Zhang CC, Olson P, Wang XQ Abstract As a multi-kinase inhibitor, sorafenib is beneficial in around 30% of hepatocellular carcinoma (HCC) patients; however, HCC patients develop acquired drug resistance quickly. Clinical benefits of sorafenib, in combination with transarterial chemoembolization (TACE), radiotherapy, and other chemodrugs are limited. We investigated the efficacy and mechanisms of Notch signaling inhibition as adjuvant to sorafenib in HCC spheroid-derived in vitro and in vivo tumor models, using the γ-secretase inhibitor (GSI), PF-03084014. The combination of PF-03084014 plus sorafenib inhibited proliferation and self-renewal of HCC spheroids (stem-like cancer cells). PF-03084014 significantly enhanced antitumor activity of sorafenib; both agents at low dose reached synergistic tumor growth suppression of HCC spheroid-derived orthotopic tumors. The Notch1-Snail1 signaling pathway contributed to sorafenib resistance via increasing epithelial-mesenchymal transition (EMT) and EMT-mediated cancer stem cell (CSC) features, such as increased expression of Snail1, N-cadherin, ABCG2, and the stem cell related genes Nanog and Oct4, and decreased expression of E-cadherin. Anti-tumor activity of the combination therapy was associated with d...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research