This co-expression has been implicated in tumour KPT-330 chemical structure progression, as FasL can act in an autocrine or juxtacrine Fas-dependent manner to promote tumour growth (Lambert et al, 2003; Houston and O’Connell, 2004). Further studies are needed to determine whether such mechanisms also apply in GIST. Gastrointestinal stromal tunour patients generally respond to therapy with imatinib, which inhibits the KIT and PDGFRA oncoproteins that appear to be initiating oncogenic events in most GISTs. However, in the long run, most patients develop resistance to imatinib therapy, as manifested by tumour progression. It appears that, although imatinib treatment induces apoptosis and causes cell cycle arrest of GIST cells, a fraction of the cells usually survive, and these surviving cells may subsequently form the nidus of an imatinib-resistant GIST, often containing secondary KIT mutations (Antonescu et al, 2005; Heinrich et al, 2006).

Therefore, novel systemic therapeutic approaches are needed to maximise GIST cell death. Targeting death receptors, such as Fas, is a promising anticancer strategy by which apoptotic cell death can be induced. Unfortunately, the introduction of therapies targeting Fas with agonistic antibodies has been hampered by liver toxicity (Ogasawara et al, 1993). However, the recently developed MegaFasL is potentially less toxic and has been shown to be active in several in vitro and in vivo models (Holler et al, 2003; Greaney et al, 2006; Etter et al, 2007).

MegaFasL is formed by crosslinking two sFasL trimers resulting in a hexameric protein that much more efficiently induces clustering of Fas on the cell surface, leading to a higher degree of multimerisation of activated receptors as compared with sFasL. As a consequence, a high local concentration of the intracellular death domains might be formed, leading to more efficient activation of caspase 8 after binding to the adaptor molecule FADD (Holler et al, 2003). We found that very low doses of MegaFasL potentiate the effect of imatinib. Therefore, even when the therapeutic window is low, systemic use of MegaFasL could still have a beneficial effect in combination with imatinib. As many GISTs tend to metastasise in the abdominal cavity, potential liver toxicity by MegaFasL might be circumvented by intraperitoneal applications to prevent MegaFasL from reaching high levels in the circulation (Stewart et al, 2002; Etter et al, 2007).

In this way, MegaFasL might be applied in combination with GSK-3 systemic imatinib. The abundant Fas expression in GISTs suggests that also MegaFasL alone might be an option for patients with primary or acquired resistance to imatinib. However, besides Fas membrane expression, one should take in account the expression of intracellular components affecting sensitivity to Fas-mediated apoptosis in these GISTs.