Mechanism of early radiographic response to imatinib in GIST.

Abstract

10049 Background: Most gastrointestinal stromal tumors (GISTs) harbor activating mutations of the receptor tyrosine kinase KIT, which is inhibited by imatinib (Novartis, Switzerland). Treatment response of GISTs to imatinib is characterized by decreased contrast uptake or tumor size on computed tomographic (CT) imaging. We sought to elucidate the mechanism by which imatinib decreases contrast enhancement of GISTs during the first 3-7 days of therapy. Methods: As part of an IRB-approved, phase II, prospective, randomized clinical trial of preoperative imatinib for GIST patients, radiographic data from 13 patients pre-/post-imatinib treatment were assessed for tumor blood flow (TBF), perfusion and transit time by perfusion CT and tumor response by positron-emission tomography (PET). Tissue specimens pre-/post-imatinib treatment were analyzed for blood vessel density (TBVD)/caliber, stem cell factor (SCF, KIT ligand) expression, KIT phosphorylation and tumor endothelial cell (TEC) apoptosis. GIST and endothelial cell lines (MVEC/HuVEC) were used to assess whether imatinib influences endothelial cell survival through the SCF/KIT signaling pathway. Results: 7 of 13 patients with PET response to imatinib demonstrated a mean 45% decrease (p=0.02) in TBF, whereas 6/13 non-responders had a mean 19% increase of TBF (p=0.21) by perfusion CT. TBVD/caliber wasn’t affected by imatinib in either group as assessed by immunofluourescence. Imatinib treatment resulted in a 14% increase in TEC apoptosis (p=0.015), compared to only 3% in the non-responders (p=0.52) by immunofluourescent TUNEL assay. Additionally, imatinib significantly blocked KIT phosphorylation of the TECs in imatinib responders but not in non-responders by immunoflourescence. In vitro, imatinib suppressed SCF expression from GIST cells, inhibited SCF-induced KIT phosphorylation by western blot and promoted apoptosis as manifested by increased caspase 3 activation in MVEC. Conclusions: The radiographic response of GISTs to imatinib correlates with decreased TBF, TEC apoptosis and SCF/KIT signaling inhibition of MVEC. These findings provide the first mechanistic support of our recently proposed criteria for evaluation of GIST response to imatinib (Choi et al, JCO 2007, 25:1760).