There is an ongoing phase 2 clinical trial that study the DR4 agonist Mapatumumab in combination with Sorafenib in subject with advanced hepatocellular carcinoma.26 However, due to the resistance of many primary cancer cells to monotherapy with TRAIL‐R agonists, as well as the lack of biomarkers to identify patients who responded to these agents, the anticancer activities of TRAIL‐based agents have exhibited limited clinical benefit. This evidence concerns the gene TNFRSF10A and hepatocellular carcinoma.