title: Erlotinib antagonizes constitutive activation of SRC family kinases and mTOR in acute myeloid leukemia.
abstract: 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.
authors: INSERM U848, Villejuif, France.
authors: Simone
authors: S
authors: Boehrer
authors: Lorenzo
authors: L
authors: Galluzzi
authors: Elodie
authors: E
authors: Lainey
authors: Cyrielle
authors: C
authors: Bouteloup
authors: Maximilien
authors: M
authors: Tailler
authors: Francis
authors: F
authors: Harper
authors: Gérard
authors: G
authors: Pierron
authors: Lionel
authors: L
authors: Adès
authors: Sylvain
authors: S
authors: Thépot
authors: Marie
authors: M
authors: Sébert
authors: Claude
authors: C
authors: Gardin
authors: Stéphane
authors: S
authors: de Botton
authors: Pierre
authors: P
authors: Fenaux
authors: Guido
authors: G
authors: Kroemer
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis; D001343:Autophagy; D014408:Biomarkers, Tumor / Q000378:metabolism; D004789:Enzyme Activation; D000069347:Erlotinib Hydrochloride; D005434:Flow Cytometry / Q000379:methods; D059585:G1 Phase Cell Cycle Checkpoints; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: C539297:3-(4-chlorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazolo(3,4-d)pyrimidin-4-amine; D014408:Biomarkers, Tumor; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D011743:Pyrimidines; D011799:Quinazolines; D013267:Stilbenes; C041525:3,3',4,5'-tetrahydroxystilbene; D000069347:Erlotinib Hydrochloride; C546842:MTOR protein, human; D019061:src-Family Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus