In intrahepatic cholangiocarcinoma (ICC), mutations in the genes encoding isocitrate dehydrogenase (IDH) lead to dependence on SRC kinase and sensitivity to dasatinib, but the underlying mechanisms are unclear. Here, Luk and colleagues identified that SRC activates p70 S6 kinase (S6K) and ribosomal protein S6 signaling independent of the mTORC1 complex. In IDH-mutant ICC, dasatinib treatment reduced S6K and S6 activity, and resistance to dasatinib was mediated by increased phosphorylation of S6. Combining dasatinib with the S6K/AKT inhibitor M2698 resulted in increased cell death in vitro and resulted in better tumor growth inhibition and survival than individual treatment in mice bearing patient-derived xenografts, suggesting a combination therapy that may be beneficial for patients with IDH-mutant ICC. —Melissa L. Norton
