Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development

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

“…Grandage et al (2005) failed to detect any relationship between PI3K/ Akt signaling upregulation and p70S6-K phosphorylation in primary AML cells. Analyses of Akt-signaling activation in primary CML samples revealed a very heterogeneous picture with several cases of p70S6-K phosphorylation, which did not correlate with Akt activation (Burchert et al, 2005). As these studies were PLC-c1-driven activation of p70S6-K pathway in CML B Markova et al carried out in distinct cellular backgrounds, we hypothesize that this PLC-g1-driven, Akt-independent pathway may be a more general mechanism, not restricted to a particular oncogene as Bcr-Abl.…”

“…In imatinib resistance, in addition to BCR-ABL resistance mutations, activated phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway has recently been implicated in the survival and expansion of leukemic cells (Burchert et al, 2005). Activation of PI3K has emerged as one of the essential signaling mechanisms contributing to Bcr-Abl leukemogenesis (Kharas and Fruman, 2005;Ren et al, 2005) by stimulating cellular proliferation, cell cycling and survival (Skorski et al, 1995(Skorski et al, , 1997.…”

The anticancer drug imatinib induces cellular autophagy

“…Treatment with the mTor-inhibitor rapamycin abrogated this activation and hence the resistance to imatinib. 43,44 Interestingly, in one study imatinib increased the rapamycin-induced cell death of serumdeprived small cell lung cancer cells. 44 We also observed an increase in autophagosome formation when cells were treated with imatinib in combination with rapamycin.…”

Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib

“…25,28 The following primary antibodies were used for probing membranes: anti-cAbl mouse monoclonal antibody, clone 24-11 (Santa Cruz Biotechnology) and anti-actin mouse mAb, clone AC-15 (Sigma-Aldrich). The secondary antibody was a horseradish peroxidase-conjugated goat anti-mouse antibody (Dako Deutschland).…”