Generation And Characterization Of A Sorafenib-Resistant Hepatocellular Carcinoma Model From Patient-Derived Tumor Xenografts

Hepatocellular carcinoma (HCC) is a common malignancy worldwide and sorafenib is a standard of care therapeutics for unresectable HCC. Although sorafenib, a multikinase inhibitor, can suppress both angiogenesis and cell proliferation, its efficacy is hampered by the emergency of drug resistance during the treatment. Thus, it is useful to understand the mechanism underlying sorafenib resistance in an animal model with resemblance of human HCC. Here, we report the generation and characterization of a sorafenib-resistant HCC xenograft model derived from patient tumors. A patient-derived xenograft (PDX) mouse model (LIX004) was treated with sorafenib. While sorafenib inhibited tumor growth at the initial stage of treatment, a few tumors regrew after prolonged sorafenib treatment. A cancer cell line (LIXC-004SR) was generated from a resistant tumor and the xenograft derived from this cell line maintained sorafenib resistance in vivo. On contrary, another cell line (LIXC-004NA) established from the treatment-naive LIX004 PDX model remained sensitive to sorafenib. We compared the gene expression profiles between these two cell lines using both cDNA microarray and qPCR and found that a class of genes involved in angiogenesis were significantly upregulated in LIXC-004SR cells vs. LIXC-004NA cells, which include those encoding secreted angiogenesis stimulators such as MMP1, FGF-5 and VEGFA. Consistently, increased angiogenesis was detected in sorafenib-resistant LIXC-004SR tumor compared to sorafenib-sensitive LIXC-004NA tumor. Furthermore, the conditional medium from LIXC-004SR cell culture could stimulate HUVEC proliferation as well as MEK,ERK and Akt phosphorylation. These results suggest that sorafenib resistance may arise by bypassing the inhibition of angiogenesis via upgregulation of pro-agiogenesis genes. The generation and molecular characterization of sorafenib-resistant tumor models could shed light on the mechanism of sorafenib resistance which may aid in the development of strategies to overcome drug resistance. Citation Format: Gang Hu, Houshan Fang, Xuzhen Tang, Kedong Ouyang, Xueyan Yang, Fubo Xie, Ke Wang, Yixin Zhang, Zhenzhou Jiang, Luyong Zhang, He Zhou, Weikang Tao. Generation and characterization of a sorafenib-resistant hepatocellular carcinoma model from patient-derived tumor xenografts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1225. doi:10.1158/1538-7445.AM2014-1225