Sphingosine kinase 2 (SphK2) and sphingosine-1-phosphate (S1P) determine regorafenib resistance through NF-kB activation in preclinical models of HCC [59], whilst low levels of secreted glycoprotein ADAMTSL5 restores regorafenib sensitivity [60]. Here, SPHK2 is linked to hepatocellular carcinoma.