Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells.
Two classes of oncogenic mutations of the c-kit tyrosine kinase have been described: the juxtamembrane domain V560G mutation, which is preferentially found in gastrointestinal stromal tumors (GISTs), and the kinase domain D816V mutation, which is highly representative of systemic mastocytosis (SM). Here we show that both mutations constitutively activate the mammalian target of rapamycin (mTOR) signaling pathway. Surprisingly, the mTOR inhibitor rapamycin induces only apoptosis in HMC-1 cells bearing the D816V but not the V560G mutation. In support of this unexpected selectivity, rapamycin inhibits the phosphorylation of 4E-BP1, a downstream substrate of the mTOR pathway, but only in D816V HMC-1 cells. Importantly, D816V mast cells isolated from SM patients or from transgenic mice are sensitive to rapamycin whereas normal human or mouse mast cells are not. Thus, rapamycin inhibition appears specific to the D816V mutation. At present there is no effective cure for SM patients with the D816V mutation. The data presented here provide a rationale to test whether rapamycin could be a possible treatment for SM and other hematologic malignancies with the D816V mutation.
Gabillot-Carré
Marion
M
CNRS UMR-8147, Université René Descartes Paris V, Hôpital Necker, 161 rue de Sèvres, 75743 Paris cedex 15, France.
Lepelletier
Yves
Y
Humbert
Martine
M
de Sepuvelda
Paulo
P
Hamouda
Nadine Ben
NB
Zappulla
Jean Pierre
JP
Liblau
Roland
R
Ribadeau-Dumas
Antoine
A
Machavoine
François
F
Letard
Sébastien
S
Baude
Cédric
C
Hermant
Aurélie
A
Yang
Ying
Y
Vargaftig
Jacques
J
Bodemer
Christine
C
Morelon
Emmanuel
E
Lortholary
Olivier
O
Recher
Christian
C
Laurent
Guy
G
Dy
Michel
M
Arock
Michel
M
Dubreuil
Patrice
P
Hermine
Olivier
O
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008407:Mast Cells / Q000187:drug effects / Q000473:pathology; D034721:Mastocytosis, Systemic / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D010597:Pharmacogenetics; D011494:Protein Kinases / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus