Mutant-tyrosine kinases sensitize Ba/F3 cells to dual PI3K/MTOR inhibition. Ba/F3 cells transfected with KIT D816Y, FLT3 ITD, D835V or BCR-ABL1 isoforms were exposed to NVP-BEZ235 (A) or NVP-BGT226 (B) in a dose-dependent manner. Dual PI3K/MTOR inhibition results in transfectant- and inhibitor-specific inhibition of cellular proliferation (XTT assay) with a higher sensitivity of cells transfected with leukemia-driving mutant-TK (KIT, FLT3, ABL1) isoforms compared to the (IL3-stimulated) parental cell line. When setting induction of apoptosis as the experimental endpoint, NVP-BEZ235 (C) was less effective compared to NVP-BGT226 (D), in all tested transfectants. IC50s, estimated by linear dose regression analysis, are provided along with several more transfectants in Table 1. (E) On the protein level, IL3-stimluated or mutant-TK Ba/F3 transfected cells show similar potent AKT dephosphorylation of Ser473 but cell strain specific cleavage of caspase 3 upon NVP-BGT226 or NVP-BEZ235 exposure. Parental, cytokine-depleted Ba/F3 cells do not express phosphorylated AKT and neither NVP-BGT226 nor NVP-BEZ235 induces cleavage of caspase 3.