PMID- 21897118
OWN - NLM
STAT- MEDLINE
DCOM- 20120319
LR  - 20211203
IS  - 1551-4005 (Electronic)
IS  - 1551-4005 (Linking)
VI  - 10
IP  - 18
DP  - 2011 Sep 15
TI  - Erlotinib antagonizes constitutive activation of SRC family kinases and mTOR in 
      acute myeloid leukemia.
PG  - 3168-75
AB  - 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 
      (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.
FAU - Boehrer, Simone
AU  - Boehrer S
AD  - INSERM U848, Villejuif, France.
FAU - Galluzzi, Lorenzo
AU  - Galluzzi L
FAU - Lainey, Elodie
AU  - Lainey E
FAU - Bouteloup, Cyrielle
AU  - Bouteloup C
FAU - Tailler, Maximilien
AU  - Tailler M
FAU - Harper, Francis
AU  - Harper F
FAU - Pierron, Gerard
AU  - Pierron G
FAU - Ades, Lionel
AU  - Ades L
FAU - Thepot, Sylvain
AU  - Thepot S
FAU - Sebert, Marie
AU  - Sebert M
FAU - Gardin, Claude
AU  - Gardin C
FAU - de Botton, Stephane
AU  - de Botton S
FAU - Fenaux, Pierre
AU  - Fenaux P
FAU - Kroemer, Guido
AU  - Kroemer G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110915
PL  - United States
TA  - Cell Cycle
JT  - Cell cycle (Georgetown, Tex.)
JID - 101137841
RN  - 0 (3-(4-chlorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazolo(3,4-d)pyrimidin-4-amine)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (MAP1LC3A protein, human)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Pyrimidines)
RN  - 0 (Quinazolines)
RN  - 0 (Stilbenes)
RN  - 6KS3LS0D4F (3,3',4,5'-tetrahydroxystilbene)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacology
MH  - Apoptosis
MH  - Autophagy
MH  - Biomarkers, Tumor/metabolism
MH  - Enzyme Activation
MH  - Erlotinib Hydrochloride
MH  - Flow Cytometry/methods
MH  - G1 Phase Cell Cycle Checkpoints
MH  - HL-60 Cells/drug effects
MH  - Humans
MH  - Leukemia, Myeloid, Acute/metabolism/*pathology
MH  - Microscopy, Electron
MH  - Microscopy, Fluorescence
MH  - Microtubule-Associated Proteins/metabolism
MH  - Phosphorylation
MH  - Pyrimidines/pharmacology
MH  - Quinazolines/*pharmacology
MH  - Signal Transduction
MH  - Sirolimus/*pharmacology
MH  - Stilbenes/pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - src-Family Kinases/*antagonists & inhibitors
EDAT- 2011/09/08 06:00
MHDA- 2012/03/20 06:00
CRDT- 2011/09/08 06:00
PHST- 2011/09/08 06:00 [entrez]
PHST- 2011/09/08 06:00 [pubmed]
PHST- 2012/03/20 06:00 [medline]
AID - 16599 [pii]
AID - 10.4161/cc.10.18.16599 [doi]
PST - ppublish
SO  - Cell Cycle. 2011 Sep 15;10(18):3168-75. doi: 10.4161/cc.10.18.16599. Epub 2011 
      Sep 15.