In vivo acquired sorafenib-resistant patient-derived tumor model displays alternative angiogenic pathways, multi-drug resistance and chromosome instability

• Published in: Oncology letters Vol. 16; no. 3; pp. 3439 - 3446
• Main Authors: Hu, Gang, Zhang, Yixin, Ouyang, Kedong, Xie, Fubo, Fang, Houshun, Yang, Xueyang, Liu, Kunyan, Wang, Zongyu, Tang, Xuzhen, Liu, Jibin, Yang, Lei, Jiang, Zhenzhou, Tao, Weikang, Zhou, He, Zhang, Luyong
• Format: Journal Article
• Language: English
• Published: Greece Spandidos Publications 01.09.2018; Spandidos Publications UK Ltd; D.A. Spandidos
• Subjects: Angiogenesis; Cell growth; Chromosome abnormalities; Chromosomes; Development and progression; Drug dosages; Drug resistance; Drug therapy; Genetic aspects; Genomes; Health aspects; Hepatocellular carcinoma; Inhibitor drugs; Kinases; Laboratory animals; Liver cancer; Patient outcomes; Patients; Sorafenib; Studies; Targeted cancer therapy; Beijing China; United States > US; China; fibroblast growth factor; sorafenib; patient-derived xenograft; acquired resistance; hepatocellular carcinoma
• ISSN: 1792-1074; 1792-1082
• DOI: 10.3892/ol.2018.9078

Acquired resistance to targeted therapies is an important clinical challenge. Research focusing on acquired resistance is hindered by the lack of relevant model systems. In the present study, the generation and characterization of an acquired sorafenib-resistant hepatocellular carcinoma (HCC) xenograft model derived from a patient tumor is reported. A cancer cell line (LIXC-004SR) was generated from a tumor that had developed following ~100 days of sorafenib treatment of a HCC patient-derived xenograft (PDX) model (LIX004). The xenograft tumors derived from this cell line demonstrated sorafenib-resistance . By contrast, a cell line (LIXC-004NA) generated from a vehicle-treated LIX004 PDX model remained sensitive to sorafenib . Following treatment with sorafenib , angiogenesis was significantly elevated in the LIXC-004SR tumors when compared with that in the LIXC-004NA tumors. The LIXC-004SR cell culture supernatant stimulated human umbilical vein endothelial cell proliferation and extracellular-signal-regulated kinase and protein kinase B phosphorylation, which can only be inhibited by the combination of sorafenib and a fibroblast growth factor receptor 1 (FGFR1) inhibitor, AZD4547. The tumor growth of the sorafenib-resistant LIXC-004SR xenograft was inhibited by the FGFR1 inhibitor , suggesting that one of the underlying mechanisms of the acquired resistance is likely due to activation of alternative angiogenic pathways. The LIXC-004SR cell line also exhibited signs of multi-drug resistance and genetic instability. Taken together, these data suggest that this model of acquired resistance from a PDX model may reflect sorafenib-resistance in certain patients and may facilitate drug resistance research, as well as contributing to the clinical prevention and management of drug resistance.