Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor

Abstract

Targeting the mammalian target of rapamycin (mTOR) is a promising strategy for cancer therapy. However, the mTOR kinase functions in two complexes, TORC1 and TORC2, neither of which is fully inhibited by the allosteric inhibitor rapamycin or analogs. We compared rapamycin with the active-site TORC1/2 inhibitor PP242, in acute leukemia models harboring the Philadelphia chromosome (Ph) translocation. We demonstrate that PP242, but not rapamycin, causes death of mouse and human leukemia cells. In vivo, PP242 delays leukemia onset and augments the effects of current front-line tyrosine kinase inhibitors, more effectively than rapamycin. Surprisingly, PP242 has much weaker effects than rapamycin on proliferation and function of normal lymphocytes. PI-103, a less selective TORC1/2 inhibitor that also targets phosphoinositide 3-kinase, is more immunosuppressive than PP242. These findings establish that Ph+ transformed cells are more sensitive than normal lymphocytes to selective TORC1/2 inhibitors, and support the development of such inhibitors for leukemia therapy.

Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia

“…17,18 However, these drugs, by inhibiting PI3K, could also result in more toxic side effects than rapamycin/rapalogs. 39 At present, the new frontier of mTOR inhibition is represented by the use of active site mTOR inhibitors, which target both mTORC1 and mTORC2, without affecting PI3K activity. 9 Accordingly, in our current study we tested the anti-leukemic activity of three compounds that directly target the mTOR catalytic domain.…”

“…9 Accordingly, in our current study we tested the anti-leukemic activity of three compounds that directly target the mTOR catalytic domain. Two of these compounds (PP-242 and OSI-027) have already been tested in other hematological cancers, including Philadelphia þ acute leukemias 39,40 and multiple myeloma, 41 and promising preclinical data were reported.…”

mTOR-Dependent Cell Survival Mechanisms

“…The mTOR ATP-competitive inhibitors are just beginning to be tested for clinical efficacy, and it is hoped that they will outperform rapamycin in the clinic. In a few preclinical studies, the mTOR catalytic inhibitors were shown to induce cell death in combination with other inhibitors (Janes et al 2010;Sini et al 2010).…”

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…Also presented in this figure are the sites of action of mTOR inhibitors, some of which have been evaluated in leukemia. 70,71 Akt inhibits tuberous sclerosis 2 (TSC2 or hamartin) function through direct phosphorylation. 72 TSC2 is a GTPase-activating protein that functions in association with the putative TSC1 (or tuberin) to inactivate the small G-protein Rheb.…”