Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs

Abstract

Abnormal protein tyrosine kinases (PTKs) cause many human leukemias. For example, BCR͞ABL causes chronic myelogenous leukemia (CML), whereas FLT3 mutations contribute to the pathogenesis of acute myelogenous leukemia. The ABL inhibitor Imatinib (Gleevec, STI571) has remarkable efficacy for treating chronic phase CML, and FLT3 inhibitors (e.g., PKC412) show similar promise in preclinical studies. However, resistance to PTK inhibitors is a major emerging problem that may limit long-term therapeutic efficacy. Development of rational combination therapies will probably be required to effect cures of these and other neoplastic disorders. Here, we report that the mTOR inhibitor rapamycin synergizes with Imatinib against BCR͞ABL-transformed myeloid and lymphoid cells and increases survival in a murine CML model. Rapamycin͞Imatinib combinations also inhibit Imatinib-resistant mutants of BCR͞ABL, and rapamycin plus PKC412 synergistically inhibits cells expressing PKC412-sensitive or -resistant leukemogenic FLT3 mutants. Biochemical analyses raise the possibility that inhibition of 4E-BP1 phosphorylation may be particularly important for the synergistic effects of PTK inhibitor͞rapamycin combinations. Addition of a mitogen-activated protein kinase kinase inhibitor to rapamycin or rapamycin plus PTK inhibitor further increases efficacy. Our results suggest that simultaneous targeting of more than one signaling pathway required by leukemogenic PTKs may improve the treatment of primary and relapsed CML and͞or acute myelogenous leukemia caused by FLT3 mutations. Similar strategies may be useful for treating solid tumors associated with mutant and͞or overexpressed PTKs.

KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway

“…These findings underscore that modulations of PI3-K pathway signaling are unpredictable and 'nonlinear', and depend on cell context. Hence, our observations in GIST are different from those reported in CML models, where synergies have been postulated for imatinib and rapamycin (Mohi et al, 2004) based on rapamycin-mediated 4EBP1 inactivation. These differences are not unprecedented, in that rapamycin has been shown to differentially effect mTOR signaling in various mammalian cells, and 4EBP1 phosphorylation can be partially rapamycin insensitive.…”

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

“…[188] Rapalogs are active in preclinical models against both TKI-naïve and -resistant CML, including blasts with the very resistant T315I mutation. [189][190][191][192] In addition, rapalogs are synergistic against CML blasts when combined with TKIs. [189][190][191] Based on the preclinical results, clinical trials investigating the activity of rapalogs are underway in both resistant CML and Ph+ ALL.…”

Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-γ1-driven activation of mTOR/p70S6-kinase pathway

“…In addition, the combination of rapamycin and imatinib was shown to synergistically suppress proliferation of leukemic cells in culture and in mouse models and therefore may be useful for treatment of imatinibresistant CML (Ly et al, 2003;Mohi et al, 2004).…”