Association Between S6K1 Phosphorylation and Cytotoxic Efficacy Of S6K1 Inhibitors

Abstract

S6K1 (ribosomal protein S6 Kinase 1) is emerging as a potential target for counteracting the glucose-dependent survival programs induced by oncogenes. In PTEN-deficient cells, previous analysis revealed that inactivating S6K1 was sufficient to reduce glycolysis and induce programmed cell death. In BCR-ABL+ cells, we found that S6K1 inactivation was cytotoxic when combined with a fatty acid oxidation inhibitor.To begin to translate these findings, we have investigated the cytotoxic efficacy of a panel of S6K1 inhibitors. Although all compounds were efficient inhibitors of S6K1 phosphorylation of downstream substrates, there was one class of inhibitors that strongly induced the phosphorylation of S6K1 itself. These inhibitors were not cytotoxic for PTEN-deficient cells. In contrast, inhibitors that avoided strong phosphorylation of S6K1 overcame the pro-survival program in PTEN-deficient cells. These results suggest that S6K1 inhibition may be beneficial as a chemotherapeutic approach, but that inhibitors should be selected to avoid the phosphorylation of S6K1 itself while also inhibiting kinase activity. Disclosures:No relevant conflicts of interest to declare.