A sorafenib derivative and novel SHP-1 agonist, SC-59, acts synergistically with radiotherapy in hepatocellular carcinoma cells through inhibition of STAT3

Radiotherapy shows limited benefit as treatment for hepatocellular carcinoma (HCC). In this study, we aimed to overcome the radioresistance of HCC by using a novel sorafenib derivative, SC-59 that targets SHP-1-related signaling. HCC cell lines (SK-Hep1, Hep3B, and Huh7) were treated with sorafenib, SC-59, radiation, sorafenib plus radiation, or SC-59 plus radiation, and then apoptosis, colony formation, signal transduction and the phosphatase activity were analyzed. The synergistic effect of radiotherapy and SC-59 was analyzed using a combination index (CI) approach. In vivo efficacy was determined in a Huh7-bearing subcutaneous model. Mice were treated with radiation (5 Gy, one fraction per day) for 4 days, SC-59 (10 mg/kg/day) for 24 days, or a combination. Tumor samples were further analyzed for p-STAT3 and SHP-1 activity. SC-59 displayed a better synergistic effect when used in combination with radiotherapy than sorafenib in HCC cell lines. SC-59 downregulated p-STAT3 and its downstream targets and increased SHP-1 phosphatase activity. Both ectopic STAT3 and inhibition of SHP-1 abolished SC-59-induced radiosensitization. Moreover, SC-59 significantly synergized radiotherapy in a Huh7 xenograft model by targeting SHP-1/STAT3 signaling. The novel sorafenib derivative, SC-59, acting as a SHP-1 agonist, displays a better synergistic effect when used in combination with radiotherapy than sorafenib for the treatment of HCC. Further clinical investigation is warranted.