期刊
CELL CYCLE
卷 10, 期 18, 页码 3168-3175出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.10.18.16599
关键词
apoptosis; BAY 61-3606; cancer; KG-1; LYN; piceatannol
类别
资金
- Fondation de France and Cent pour Sang la Vie
- Apo-Sys
- Post Accueil INSERM
- AXA Chair for Longevity Research
- Canceropole Ile-de-France
- Institut National du Cancer (INCa)
- Fondation Bettencourt-Schueller
- Fondation de France, Association Laurette Fugain
- Agence National de la Recherche
- Fondation pour la Recherche Medicale
- LabEx Immuno-Oncology
- European Commission
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-alpha]pyrimidin-4-amine (PP 2). 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, PP 2 and the mTOR inhibitor rapamycin had a similar cell cycle-arresting activity as 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.
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