S6K1 determines the metabolic requirements for BCR-ABL survival

In Chronic Myelogenous Leukemia, the constitutive activation of the BCR-ABL kinase transforms cells to an “addicted” state that requires glucose metabolism for survival. We investigated S6K1, a protein kinase that drives glycolysis in leukemia cells, as a target for counteracting glucose-dependent survival induced by BCR-ABL. BCR-ABL potently activated S6K1-dependent signaling and glycolysis. Although S6K1 knockdown or rapamycin treatment suppressed glycolysis in BCR-ABL transformed cells, these treatments did not induce cell death. Instead, loss of S6K1 triggered compensatory activation of fatty acid oxidation, a metabolic program that can support glucose-independent cell survival. Fatty acid oxidation in response to S6K1-inactivation required the expression of the fatty acid transporter Cpt1c, which was recently linked to rapamycin resistance in cancer. Finally, addition of an inhibitor of fatty acid oxidation significantly enhanced cytotoxicity in response to S6K1 inactivation. These data indicate that S6K1 dictates the metabolic requirements mediating BCR-ABL survival and provide a rationale for combining targeted inhibitors of signal transduction with strategies to interrupt oncogene-induced metabolism.