Oncotarget

Research Papers:

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

Xuran Yang, Wei Xia, Lin Chen, Chuan Xing Wu, Cathy C. Zhang, Peter Olson and Xiao Qi Wang _

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Oncotarget. 2018; 9:34996-35007. https://doi.org/10.18632/oncotarget.26209

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Abstract

Xuran Yang1, Wei Xia1, Lin Chen1, Chuan Xing Wu1, Cathy C. Zhang2, Peter Olson2 and Xiao Qi Wang1

1Department of Surgery, The University of Hong Kong, Hong Kong, China

2Oncology Research Unit, Pfizer Global Research and Development, La Jolla, California, USA

Correspondence to:

Xiao Qi Wang, email: [email protected]

Keywords: GSI; PF-03084014; sorafenib; antitumor; HCC

Received: August 10, 2018     Accepted: September 21, 2018     Published: October 09, 2018

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 decreased expression of survival signals (Mek/Erk, PI3K/Akt) and reduced microvessel density. PF-03084014 plus sorafenib targets Notch1-Snail1 signaling to reverse EMT and EMT-mediated CSC stemness in the tumors. These synergistic effects provide a rationale to utilize GSIs, in combination with sorafenib, as a new therapeutic strategy for the treatment of HCC.


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