Erlotinib antagonizes constitutive activation of SRC family kinases and mTOR in acute myeloid leukemia

Tyrosine kinases such as SRC family kinases (SFKs) as well as the mammalian target of rapamycin (mTOR) serine/threonine kinase are often constitutively activated in acute myeloid leukemia (AML) and hence constitute potential therapeutic targets. Here we demonstrate that the epidermal growth factor r...

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Published in:Cell cycle (Georgetown, Tex.) Tex.), 2011-09, Vol.10 (18), p.3168-3175
Main Authors: Boehrer, Simone, Galluzzi, Lorenzo, Lainey, Elodie, Bouteloup, Cyrielle, Tailler, Maximilien, Harper, Francis, Pierron, Gérard, Adès, Lionel, Thépot, Sylvain, Sébert, Marie, Gardin, Claude, de Botton, Stéphane, Fenaux, Pierre, Kroemer, Guido
Format: Article
Language:English
Subjects:
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Apoptosis
Autophagy
Binding
Biology
Biomarkers, Tumor - metabolism
Bioscience
Calcium
Cancer
Cell
Cycle
Enzyme Activation
Erlotinib Hydrochloride
Flow Cytometry - methods
G1 Phase Cell Cycle Checkpoints
HL-60 Cells - drug effects
Humans
Landes
Leukemia, Myeloid, Acute - metabolism
Leukemia, Myeloid, Acute - pathology
Microscopy, Electron
Microscopy, Fluorescence
Microtubule-Associated Proteins - metabolism
Organogenesis
Phosphorylation
Proteins
Pyrimidines - pharmacology
Quinazolines - pharmacology
Signal Transduction
Sirolimus - pharmacology
src-Family Kinases - antagonists & inhibitors
Stilbenes - pharmacology
TOR Serine-Threonine Kinases - antagonists & inhibitors
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Summary:Tyrosine kinases such as SRC family kinases (SFKs) as well as the mammalian target of rapamycin (mTOR) serine/threonine kinase are often constitutively activated in acute myeloid leukemia (AML) and hence constitute potential therapeutic targets. Here we demonstrate that the epidermal growth factor receptor (EGFR) inhibitor erlotinib, which has previously been shown to mediate antiproliferative/cytotoxic off-target effects in myelodysplastic syndrome (MDS) and AML blasts, reduces SFK overactivation. Erlotinib induced an arrest in the G 1 phase of the cell cycle that, in cells with constitutive SFK activation, could be recapitulated by chemical inhibition of SFKs with 3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-α]pyrimidin-4-amine (PP2). Moreover, erlotinib inhibited the phosphorylation of mTOR targets like p70 SK6 , stimulated the maturation of the autophagic marker LC3 and promoted the formation of autophagosomes. Notably, PP2 and the mTOR inhibitor rapamycin had a similar cell cycle-arresting activity to erlotinib, but neither of these compounds alone induced significant levels of cell death. Altogether, these results suggest that the therapeutic off-target effect of erlotinib may be linked to, yet cannot be entirely explained by, the inhibition of oncogenic signaling via SFKs and mTOR. Thus, combination therapies with erlotinib and rapamycin might be beneficial for MDS and AML patients.
ISSN:1538-4101
1551-4005
DOI:10.4161/cc.10.18.16599