Anti-tumor effects of Notch pathway in Gastrointestinal Stromal Tumors
Menée sur des lignées cellulaires, cette étude suggère qu'un traitement activant la voie de signalisation Notch1 représente une stratégie thérapeutique intéressante pour le traitement des patients atteints d'une tumeur stromale gastro-intestinale ayant développé une résistance à l'imatinib
Gastrointestinal Stromal Tumors (GISTs) are driven by gain-of-function mutations of KIT. The introduction of imatinib has significantly extended survival for patients. However, most patients develop resistances. Notch signaling is a conserved developmental pathway known to play a critical role in the development of several cancers, functioning as a tumor promoter or a tumor suppressor. Given that the normal progenitor cell for GIST, the Interstitial Cell of Cajal, has characteristics similar to those of cells of neuroendocrine origin, we hypothesized that Notch pathway impacts the biology of GIST cells. In the present study, we retrovirally and pharmacologically manipulated the Notch pathway in human GIST cells. We also performed a retrospective analysis of a cohort on 15 primary tumors to determine the role of Hes1, a major target gene of Notch, as a prognostic marker for GIST. Constitutively active intracellular domain of Notch1 (ICN-1) expression potently induced growth arrest and downregulated KIT expression in vitro. Additionally, treatment with the histone deacetylase inhibitor SAHA caused dose-dependent upregulation of Notch1 expression and a parallel decrease in viability in these cells. Retroviral silencing of downstream targets of Notch (dominant negative Hes-1) and pharmacological inhibition of Notch activation (γ secretase inhibition) partially rescued GIST cells from SAHA treatment. GIST patients with high Hes1 mRNA levels have a significantly longer relapse-free survival. These results identify a novel anti-tumor effect of Notch1 and cross-talk between the Notch and KIT pathways. Thus, activation of this pathway by treatment with HDAC inhibitors is an appealing potential therapeutic strategy for GISTs.
http://carcin.oxfordjournals.org/content/early/2012/07/04/carcin.bgs221.abstract