Efficacy Analysis of the Novel Dual PI3K-MTORC1/2 Inhibitors NVP-BGT226 and NVP-BEZ235 in Acute Leukemia.

Dysregulation of the PI3Kinase/AKT pathway is involved in the pathogenesis of many human malignancies. Constitutive phosphorylation of AKT is frequently found in acute leukemia but the underlying molecular mechanisms remain unclear and mutations in the PI3K/AKT pathway are uncommon in leukemia. In some cases, constitutive AKT activation can be linked to gain-of function tyrosine kinase mutations upstream of the PI3K/AKT pathway. While inhibitors of the PI3K/AKT pathway appear attractive for tumor therapy, so far response rates to PI3K inhibitor treatment of various neoplasms are moderate. Furthermore, MTORC1 inhibitors, targeting downstream of AKT, have the disadvantage of activating AKT via feed-back mechanisms. We here comparatively studied two novel dual PI3K-MTORC1/2 inhibitors, NVP-BEZ235 and NVP-BGT226, with regard to their ability to inhibit proliferation and to induce apoptosis in different leukemia cell models as well as in primary leukemia samples.

Expression of phospho-AKT protein levels was determined in 74 leukemia patient blood and bone marrow samples by flow cytometry. Protein and functional viability assays evaluating the effects of NVP-BEZ235 and NVP-BGT226 were performed in several leukemia cell lines, mutant-tyrosine kinase cell models and with primary leukemia blasts and bone marrow cells. Antineoplastic activity was assessed in proliferation and apoptosis experiments. Immunoblots were performed to confirm consecutive suppression of AKT signaling.

AKT is generally expressed in acute leukemia at significantly higher levels as compared to healthy donor samples (p < 0.05, students t-test). Dual targeting of the PI3K-AKT-MTOR pathway profoundly inhibited AKT signaling, leading to antiproliferative effects in vitro and ex vivo. Moreover, both agents potently induced apoptosis in a subset of leukemia samples with BGT226 being the more effective agent and displaying IC50s at the low nanomolar level. Cell cycle analyses revealed that NVP-BGT226 overrides the G1-arrest observed with NVP-BEZ235-treated cells. Importantly, normal mononuclear cells revealed lower phospho-AKT expression levels and relative insensitivity towards dual PI3K-MTORC1/2 inhibition.

Our data provide a strong rationale for clinical evaluation of the tested dual PI3K-MTORC1/2 inhibitors in acute leukemias.

No relevant conflicts of interest to declare.