PMID- 17546049
OWN - NLM
STAT- MEDLINE
DCOM- 20080109
LR  - 20220321
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 26
IP  - 54
DP  - 2007 Nov 29
TI  - KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal 
      tumor: PI3-kinase/AKT is a crucial survival pathway.
PG  - 7560-8
AB  - Most gastrointestinal stromal tumor (GIST) patients respond to KIT inhibition 
      with imatinib, yet will eventually exhibit resistance. Imatinib-resistance 
      mechanisms are heterogeneous, and little is known about KIT functional roles in 
      imatinib-resistant GIST. Biological consequences of biochemical inhibition of 
      KIT, phosphatidyl-inositol-3-kinase (PI3-K), PLCgamma, MAPK/ERK 
      kinase/mitogen-activated protein kinase (MEK/MAPK), mammalian target of rapamycin 
      (mTOR) and JAK were determined by immunoblotting for protein activation, and by 
      cell proliferation and apoptosis assays in GIST cell lines from 
      imatinib-sensitive GIST (GIST882), imatinib-resistant GISTs (GIST430 and GIST48) 
      and KIT-negative GIST (GIST62). KIT activation was 3- to 6-fold higher in GIST430 
      and GIST48 than in GIST882, whereas total KIT expression was comparable in these 
      three GIST lines. In addition to the higher set point for KIT activation, GIST430 
      and GIST48 had intrinsic imatinib resistance. After treatment with 1 muM 
      imatinib, residual KIT activation was 6- and 2.8-fold higher in GIST430 and 
      GIST48, respectively, compared to GIST882. In all GIST lines, cell growth arrest 
      resulted from PI3-K inhibition, and - to a lesser extent - from MEK/MAPK and mTOR 
      inhibition. Inhibition of JAK/STAT or PLCgamma did not affect cell proliferation. 
      Similarly, only PI3-K inhibition resulted in substantial apoptosis in the 
      imatinib-resistant GISTs. We conclude that GIST secondary KIT mutations can be 
      associated with KIT hyperactivation and imatinib resistance. Targeting critical 
      downstream signaling proteins, such as PI3-K, is a promising therapeutic strategy 
      in imatinib-resistant GISTs.
FAU - Bauer, S
AU  - Bauer S
AD  - Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, MA 02155, USA. sebastian.bauer@uni-due.de
FAU - Duensing, A
AU  - Duensing A
FAU - Demetri, G D
AU  - Demetri GD
FAU - Fletcher, J A
AU  - Fletcher JA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070604
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzamides)
RN  - 0 (Piperazines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-kit)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Antineoplastic Agents/pharmacology
MH  - Benzamides
MH  - Cell Cycle
MH  - Cell Line, Tumor
MH  - Cell Survival/*physiology
MH  - Drug Resistance, Neoplasm
MH  - Enzyme Activation
MH  - *Gastrointestinal Stromal Tumors
MH  - Humans
MH  - Imatinib Mesylate
MH  - Kinetics
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Piperazines/*pharmacology
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Protein Kinases/metabolism
MH  - Proto-Oncogene Proteins c-kit/*physiology
MH  - Pyrimidines/*pharmacology
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases
EDAT- 2007/06/05 09:00
MHDA- 2008/01/10 09:00
CRDT- 2007/06/05 09:00
PHST- 2007/06/05 09:00 [pubmed]
PHST- 2008/01/10 09:00 [medline]
PHST- 2007/06/05 09:00 [entrez]
AID - 1210558 [pii]
AID - 10.1038/sj.onc.1210558 [doi]
PST - ppublish
SO  - Oncogene. 2007 Nov 29;26(54):7560-8. doi: 10.1038/sj.onc.1210558. Epub 2007 Jun 
      4.