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Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells
Marion Gabillot-Carré1, Yves Lepelletier, Martine Humbert
1CNRS UMR-8147, Université René Descartes Paris V, Hôpital Necker, 161 rue de Sèvres, 75743 Paris cedex 15, France.
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.
Insights
The c-kit V560G and D816V mutations activate mTOR signaling. Rapamycin selectively induces apoptosis in D816V-mutated cells, suggesting it may treat systemic mastocytosis (SM).
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Two oncogenic c-kit mutations, V560G (Gastrointestinal Stromal Tumors) and D816V (Systemic Mastocytosis), activate the mammalian target of rapamycin (mTOR) pathway.
- Current treatments for Systemic Mastocytosis (SM) with the D816V mutation are limited.
Purpose of the Study:
- To investigate the differential effects of the mTOR inhibitor rapamycin on cells with V560G and D816V c-kit mutations.
- To determine the potential of rapamycin as a targeted therapy for SM.
Main Methods:
- Constitutive activation of mTOR signaling by V560G and D816V mutations was assessed.
- Apoptosis induction by rapamycin in HMC-1 cells with D816V or V560G mutations was evaluated.
- Phosphorylation of the mTOR substrate 4E-BP1 was measured in response to rapamycin.
- Sensitivity of primary D816V mast cells (from patients and mice) to rapamycin was compared to normal mast cells.
Main Results:
- Both V560G and D816V mutations constitutively activate the mTOR pathway.
- Rapamycin selectively induced apoptosis in HMC-1 cells harboring the D816V mutation, but not the V560G mutation.
- Rapamycin inhibited 4E-BP1 phosphorylation specifically in D816V HMC-1 cells.
- Primary D816V mast cells were sensitive to rapamycin, while normal mast cells were resistant.
Conclusions:
- Rapamycin exhibits selective efficacy against the D816V c-kit mutation.
- These findings provide a strong rationale for investigating rapamycin as a therapeutic agent for Systemic Mastocytosis and other D816V-driven hematologic malignancies.
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