title: Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells.
abstract: 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.
authors.affiliation: CNRS UMR-8147, Université René Descartes Paris V, Hôpital Necker, 161 rue de Sèvres, 75743 Paris cedex 15, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gabillot-Carré
authors.forename: Yves
authors.initials: Y
authors.lastname: Lepelletier
authors.forename: Martine
authors.initials: M
authors.lastname: Humbert
authors.forename: Paulo
authors.initials: P
authors.lastname: de Sepuvelda
authors.forename: Nadine Ben
authors.initials: NB
authors.lastname: Hamouda
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Zappulla
authors.forename: Roland
authors.initials: R
authors.lastname: Liblau
authors.forename: Antoine
authors.initials: A
authors.lastname: Ribadeau-Dumas
authors.forename: François
authors.initials: F
authors.lastname: Machavoine
authors.forename: Sébastien
authors.initials: S
authors.lastname: Letard
authors.forename: Cédric
authors.initials: C
authors.lastname: Baude
authors.forename: Aurélie
authors.initials: A
authors.lastname: Hermant
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Jacques
authors.initials: J
authors.lastname: Vargaftig
authors.forename: Christine
authors.initials: C
authors.lastname: Bodemer
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Morelon
authors.forename: Olivier
authors.initials: O
authors.lastname: Lortholary
authors.forename: Christian
authors.initials: C
authors.lastname: Recher
authors.forename: Guy
authors.initials: G
authors.lastname: Laurent
authors.forename: Michel
authors.initials: M
authors.lastname: Dy
authors.forename: Michel
authors.initials: M
authors.lastname: Arock
authors.forename: Patrice
authors.initials: P
authors.lastname: Dubreuil
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
mesh_terms: 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
chemical_list: D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus