In the present study, we demonstrated that (i) PDK1 is an independent driver of the PI3K/AKT/mTOR signaling pathway and its aberrant expression characterizes poorly differentiated aggressive HCC cells, with (ii) altered PDK1 expression being sufficient for the deactivation of the PI3K/PDK/AKT/mTOR oncogenic signaling, and sensitization of aggressive HCC cells to radiotherapy. The gene discussed is PDK1; the disease is hepatocellular carcinoma.