Additionally we tested the GIST solid tumor cell line GIST882 with a second cell line, which was established from a patient despite with relapsing GIST under imatinib therapy. This cell line harbors a primary homo zygous juxtamembrane KIT mutation plus a sec ondary heterozygous imatinib insensitive activation loop mutation. Indeed, in our experiments, NVP BEZ235 as well as NVP BGT226 potently induced apoptosis irrespective of the sensitivity profile towards TKI with NVP BGT226 again being the more potent Inhibitors,Modulators,Libraries inhibitor. Together, dual PI3KMTOR inhibitors such as NVP BGT226 or NVP BEZ235 may be of special clin ical value in the desperate case of tumor progress due to TKI resistance, which is an ever increasing problem in the treatment of relapsed acute leukemia.

Inhibitors,Modulators,Libraries The underlying molecular mechanisms determining the susceptibility of cells towards induction of apoptosis as well as sensitivity towards NVP BGT226 or NVP BEZ235 targets is elusive and will need to be answered in future studies. Most importantly however, we did show that dual inhi bition of pan class I PI3Kinases plus MTOR12 com plexes does translate into a genuine antiproliferative but Inhibitors,Modulators,Libraries also proapoptotic effect in native leukemia cells treated ex vivo with NVP BGT226 being the more potent drug with regard to induction of apoptosis. Augmented phosphorylation of AKT rather than mere expression of AKT protein levels seemed to be a prerequisite for treat ment response. However, this observation will need prospective validation. Furthermore, efficacy was not Inhibitors,Modulators,Libraries re stricted to leukemia samples with identified genomic mechanisms of AKT activation, suggesting alternative mechanisms of acti vation yet to be identified.

Of note, among the Inhibitors,Modulators,Libraries native leukemia samples treated successfully ex vivo with either agent were cases from patients with poor prognostic features lacking effective therapeutic options. For example, both agents were effective in AML with mutant FLT3, including a patient with TKI resistant FLT3 ITD positive AML who had relapsed after allogeneic stem cell transplantation. Other refractory AML cases with ex vivo sensitivity of cells to PI3KMTOR inhibition included a relapsed elderly patient with MLL rearranged AML. In this con text, it has been shown that MLL rearrangements associ ate with high EVI1 expression, which predicts for dismal prognosis.

Further, Yoshimi and colleagues re cently have demonstrated that EVI1 activates AKT signaling due to loss of PTEN activity. As there are currently no effective therapy options for treat ment of EVI1 associated AML, targeting the PI3K AKTMTOR pathway may be things particularly of interest. Preliminary data of an early phase I trial of NVP BEZ235 in the treatment of advanced unresectable solid tumors demonstrated good tolerability with no dose limiting toxicities.