PMID- 19502802
OWN - NLM
STAT- MEDLINE
DCOM- 20090827
LR  - 20211028
IS  - 1551-4005 (Electronic)
IS  - 1538-4101 (Print)
IS  - 1551-4005 (Linking)
VI  - 8
IP  - 13
DP  - 2009 Jul 1
TI  - Cancer cells harboring MET gene amplification activate alternative signaling 
      pathways to escape MET inhibition but remain sensitive to Hsp90 inhibitors.
PG  - 2050-6
AB  - Hepatocyte growth factor/scatter factor (HGF/SF) receptor c-Met is implicated in 
      growth, invasion and metastasis of many tumors. Tumor cells harboring MET gene 
      amplification are initially sensitive to c-Met tyrosine kinase inhibitors (TKI), 
      but escape from long-term treatment has not been investigated. C-Met is a client 
      of heat shock protein 90 (Hsp90) and is destabilized by Hsp90 inhibitors, 
      suggesting that these drugs may inhibit tumors driven by MET amplification, 
      although tumor escape under these conditions also has not been explored. Here, we 
      evaluated the initial inhibitory effects of, and the likelihood of escape from, 
      the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) and the c-Met 
      TKI SU11274, using two cell lines harboring MET gene amplification. 17-AAG 
      inhibited cell growth in both cell lines and induced substantial apoptosis, 
      whereas SU11274 was only growth inhibitory in one cell line. In both cell lines, 
      c-Met-dependent Akt, Erk and/or STAT3 signaling, as well as activation of the 
      EGFR family, resumed shortly after treatment with c-Met TKI despite sustained 
      c-Met inhibition. PKC delta upregulation may participate in reactivation of c-Met 
      downstream signaling in both cell lines. In contrast to c-Met TKI, 17-AAG 
      destabilized c-Met protein and durably blocked reactivation of downstream 
      signaling pathways and EGFR family members. Our data demonstrate that downstream 
      signaling in tumor cells overexpressing c-Met is not stably suppressed by c-Met 
      TKI, even though c-Met remains fully inhibited. In contrast, Hsp90 inhibitors 
      provide long-lasting suppression of c-Met-dependent signaling, and these drugs 
      should be further evaluated in tumors driven by MET gene amplification.
FAU - Wang, Suiquan
AU  - Wang S
AD  - Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      Bethesda, MD, USA.
FAU - Pashtan, Itai
AU  - Pashtan I
FAU - Tsutsumi, Shinji
AU  - Tsutsumi S
FAU - Xu, Wanping
AU  - Xu W
FAU - Neckers, Len
AU  - Neckers L
LA  - eng
GR  - Z01 BC011032/ImNIH/Intramural NIH HHS/United States
GR  - Z01 SC010074/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
DEP - 20090727
PL  - United States
TA  - Cell Cycle
JT  - Cell cycle (Georgetown, Tex.)
JID - 101137841
RN  - 0 
      (((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide))
RN  - 0 (Benzoquinones)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (Indoles)
RN  - 0 (Lactams, Macrocyclic)
RN  - 0 (Piperazines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Receptors, Growth Factor)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (Sulfonamides)
RN  - 4GY0AVT3L4 (tanespimycin)
RN  - EC 2.7.10.1 (MET protein, human)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.13 (Protein Kinase C-delta)
SB  - IM
CIN - Cell Cycle. 2009 Sep 1;8(17):2682. PMID: 19717982
MH  - Apoptosis
MH  - Benzoquinones/*pharmacology
MH  - Gene Amplification
MH  - HSP90 Heat-Shock Proteins/*antagonists & inhibitors/metabolism
MH  - Humans
MH  - Indoles/*pharmacology
MH  - Lactams, Macrocyclic/*pharmacology
MH  - Neoplasms/*enzymology/genetics/metabolism
MH  - Piperazines/*pharmacology
MH  - Protein Kinase C-delta/metabolism
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins/antagonists & inhibitors/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Proto-Oncogene Proteins c-met
MH  - Receptor Protein-Tyrosine Kinases/antagonists & inhibitors/genetics/*metabolism
MH  - Receptors, Growth Factor/antagonists & inhibitors/genetics/*metabolism
MH  - STAT3 Transcription Factor/metabolism
MH  - Signal Transduction
MH  - Sulfonamides/*pharmacology
MH  - Tumor Cells, Cultured
PMC - PMC7282701
MID - NIHMS1589604
EDAT- 2009/06/09 09:00
MHDA- 2009/08/28 09:00
PMCR- 2020/06/09
CRDT- 2009/06/09 09:00
PHST- 2009/06/09 09:00 [entrez]
PHST- 2009/06/09 09:00 [pubmed]
PHST- 2009/08/28 09:00 [medline]
PHST- 2020/06/09 00:00 [pmc-release]
AID - 8861 [pii]
AID - 10.4161/cc.8.13.8861 [doi]
PST - ppublish
SO  - Cell Cycle. 2009 Jul 1;8(13):2050-6. doi: 10.4161/cc.8.13.8861. Epub 2009 Jul 27.