PMID- 16908864
OWN - NLM
STAT- MEDLINE
DCOM- 20060929
LR  - 20211203
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 103
IP  - 34
DP  - 2006 Aug 22
TI  - Oncogenic Kit signaling and therapeutic intervention in a mouse model of 
      gastrointestinal stromal tumor.
PG  - 12843-8
AB  - Kit receptor-activating mutations are critical in the pathogenesis of 
      gastrointestinal stromal tumors (GIST). We investigated mechanisms of oncogenic 
      Kit signaling and the consequences of therapeutic intervention in a mouse model 
      of human GIST. Treatment of GIST mice with imatinib decreased cell proliferation 
      and increased apoptosis in the tumor. Analysis of tumor tissue from 
      imatinib-treated mice showed diminished phosphatidylinositol 3-kinase 
      (PI3-kinase) and mammalian target of rapamycin (mTOR) signaling suggesting that 
      oncogenic Kit signaling critically contributes to the translational response in 
      GIST. Treatment with RAD001 (everolimus), an mTOR inhibitor, diminished the 
      translational response and cell proliferation in tumor lesions, pointing to mTOR 
      inhibition as a therapeutic approach for imatinib-resistant GIST. Analysis of RNA 
      expression profiles in GIST lesions with and without imatinib treatment showed 
      changes in expression of IFN-inducible genes and cell cycle regulators. These 
      results convincingly show that KitV558Delta/+ mice represent a unique faithful 
      mouse model of human familial GIST, and they demonstrate the utility of these 
      mice for preclinical investigations and to elucidate oncogenic signaling 
      mechanisms by using genetic approaches and targeted pharmacological intervention.
FAU - Rossi, Ferdinand
AU  - Rossi F
AD  - Department of Developmental Biology, Computational Biology Center, and Molecular 
      Cytology Facility, Sloan-Kettering Institute, New York, NY 10021, USA.
FAU - Ehlers, Imke
AU  - Ehlers I
FAU - Agosti, Valter
AU  - Agosti V
FAU - Socci, Nicholas D
AU  - Socci ND
FAU - Viale, Agnes
AU  - Viale A
FAU - Sommer, Gunhild
AU  - Sommer G
FAU - Yozgat, Yasemin
AU  - Yozgat Y
FAU - Manova, Katia
AU  - Manova K
FAU - Antonescu, Cristina R
AU  - Antonescu CR
FAU - Besmer, Peter
AU  - Besmer P
LA  - eng
GR  - R01 CA102774/CA/NCI NIH HHS/United States
GR  - R01 DK055748/DK/NIDDK NIH HHS/United States
GR  - CA 102774/CA/NCI NIH HHS/United States
GR  - HL/DK55748/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20060814
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Benzamides)
RN  - 0 (Piperazines)
RN  - 0 (Pyrimidines)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-kit)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Benzamides
MH  - Cell Proliferation/drug effects
MH  - *Disease Models, Animal
MH  - Down-Regulation
MH  - Everolimus
MH  - Gastrointestinal Stromal Tumors/*drug therapy/genetics/*metabolism/pathology
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic
MH  - Imatinib Mesylate
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Phosphorylation
MH  - Piperazines/therapeutic use
MH  - Protein Kinases/metabolism
MH  - Proto-Oncogene Proteins c-kit/genetics/*metabolism
MH  - Pyrimidines/therapeutic use
MH  - *Signal Transduction
MH  - Sirolimus/analogs & derivatives/therapeutic use
MH  - TOR Serine-Threonine Kinases
PMC - PMC1568935
COIS- Conflict of interest statement: No conflicts declared.
EDAT- 2006/08/16 09:00
MHDA- 2006/09/30 09:00
PMCR- 2007/02/22
CRDT- 2006/08/16 09:00
PHST- 2006/08/16 09:00 [pubmed]
PHST- 2006/09/30 09:00 [medline]
PHST- 2006/08/16 09:00 [entrez]
PHST- 2007/02/22 00:00 [pmc-release]
AID - 0511076103 [pii]
AID - 3023 [pii]
AID - 10.1073/pnas.0511076103 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12843-8. doi: 
      10.1073/pnas.0511076103. Epub 2006 Aug 14.