Abstract 3239: The Notch pathway as a new target in gastrointestinal stromal tumors

Abstract

Abstract Small molecule kinase inhibitors have dramatically improved the survival of patients with Gastrointestinal Stromal Tumors (GIST), yet most patients develop resistance, urging us to understand better the molecular mechanisms underlying this disease and identify new therapeutic strategies. 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 a previous study, we demonstrated that constitutively active intracellular domain of Notch1 (ICN-1) induced growth arrest in GIST cell lines. Here we report that ICN-1 downregulated KIT protein by a flow cytometric analysis in the three cell lines analyzed (GIST-T1, GIST882, GIST48IM). In parallel, inhibitions of Hes1, a major target gene of ICN-1, with a dominant negative construct, upregulated KIT protein expression in vitro (60% increase on western blot). This anti-tumor effect of Notch1 in GIST leads to a therapeutic opportunity as we showed in the present study that treatment with the histone deacetylase inhibitor, SAHA, caused a dose-dependent upregulation of Notch1 (6 fold increase of the mRNA with SAHA 2 µm/L on GIST-T1, P<0.05), downregulation of KIT and pKIT (9 fold decrease of pKIT on western blot with SAHA 2 µm/L on GIST-T1), increase in apoptosis (25-fold increase in the sub-G1 population with SAHA 2 µmol/L on GIST-T1, P<0.05), decrease in viability of the GIST cells (IC50 = 2 µmol/L on GIST-T1).To confirm the clinical relevance of the Notch pathway on GIST, we performed a retrospective analysis on 15 pre-treated patient tumors and showed that GIST patients with high Hes1 mRNA levels have a significantly longer relapse-free survival than the one with low Hes1 mRNA levels (median of 37 months for the low group versus median not reached at >80 months for the high group; P=0.005). These results identify a novel anti-tumor effect of Notch1 via a crosstalk between the Notch1 and KIT pathways in GIST cells. This finding may lead to new therapeutic strategies for GIST patients, in particular after failure of tyrosine kinase inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3239. doi:1538-7445.AM2012-3239