Journal
CANCER RESEARCH
Volume 81, Issue 12, Pages 3229-3240Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-21-0184
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Funding
- RGC General Research Fund [15103817]
- Theme-based Research Scheme project [T12-704/16-R]
- Project of Strategic Importance (PolyU
- FAST-5)
- Research Impact Fund [R5050-18F]
- Centralized Animal Facility at the Hong Kong Polytechnic University
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This study identified a EPHB2/beta-catenin/TCF1 positive feedback loop that enhances cancer stemness and sorafenib resistance in HCC, providing a targetable axis to combat acquired drug resistance in HCC.
The survival benefit derived from sorafenib treatment for patients with hepatocellular carcinoma (HCC) is modest due to acquired resistance. Targeting cancer stem cells (CSC) is a possible way to reverse drug resistance, however, inhibitors that specifically target liver CSCs are limited. In this study, we established two sorafenib-resistant, patient-derived tumor xenografts (PDX) that mimicked development of acquired resistance to sorafenib in patients with HCC. RNA-sequencing analysis of sorafenib-resistant PDXs and their corresponding mock controls identified EPH receptor 132 (EPHB2) as the most significantly upregulated kinase. EPHB2 expression increased stepwise from normal liver tissue to fibrotic liver tissue to HCC tissue and correlated with poor prognosis. Endogenous EPHB2 knockout showed attenuation of tumor development in mice. EPHB2 regulated the traits of liver CSCs; similarly, sorted EPHB2-High HCC cells were endowed with enhanced CSC properties when compared with their EPHB2-Low counterparts. Mechanistically, EPHB2 regulated cancer stemness and drug resistance by driving the SRC/AKT/GSK3 beta/beta-catenin signaling cascade, and EPHB2 expression was regulated by TCF I via promoter activation, forming a positive Wnt/beta-catenin feedback loop. Intravenous administration of rAAV-8-shEPHB2 suppressed HCC tumor growth and significantly sensitized HCC cells to sorafenib in an NRAS/AKT-driven HCC immunocompetent mouse model. Targeting a positive feedback loop involving the EPHB2/beta-catenin axis may be a possible therapeutic strategy to combat acquired drug resistance in HCC. Significance: This study identifies a EPHB2/13-catenin/TCF1 positive feedback loop that augments cancer stemness and sorafenib resistance in HCC, revealing a targetable axis to combat acquired drug resistance in HCC.
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