Mol Cancer
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Dysregulation of the PI3Kinase/AKT pathway is involved in the pathogenesis of many human malignancies. In acute leukemia, the AKT pathway is frequently activated, however mutations in the PI3K/AKT pathway are uncommon. In some cases, constitutive AKT activation can be linked to gain-of-function tyrosine kinase (TK) mutations upstream of the PI3K/AKT pathway. Inhibitors of the PI3K/AKT pathway are attractive candidates for cancer drug development, but so far clinical efficacy of PI3K inhibitors against various neoplasms has been moderate. Furthermore, specific MTORC1 inhibitors, acting downstream of AKT, have the disadvantage of activating AKT via feed-back mechanisms. We now evaluated the antitumor efficacy of NVP-BGT226, a novel dual pan-PI3K and MTORC1/2 inhibitor, in acute leukemia. ⋯ Our data suggest a favorable antileukemic profile for NVP-BGT226 compared to NVP-BEZ235--which provides a strong rationale for clinical evaluation of the dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia.