Several mechanisms that contribute to acquired refractoriness to sorafenib have been reported [13,35], with examples including the PI3K/AKT [36,37], Raf/Mek/ERK [38], and Jak/Stat3 [39,40] signaling pathways; activation of hypoxia-inducible pathways [41]; epithelial–mesenchymal transition [42]; enrichment of tumor-initiating cell population [43]; microenvironmental and metabolic derangement [44]; and autophagy [45]. The gene discussed is STAT3; the disease is neoplasm.