TRAIL-receptor and proteasome targeted therapies in non-small cell lung cancer

PhD ceremony: Ms. J.H. Stegehuis, 13.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: TRAIL-receptor and proteasome targeted therapies in non-small cell lung cancer

Promotor(s): prof. E.G.E. de Vries

Faculty: Medical Sciences

The natural occurring protein TRAIL is important in the battle against cancer. TRAIL binds to healthy cells where it but does not cause damage, whereas binding to tumour cells may lead to their elimination. Various TRAIL-receptor targeting drugs are likely to increase the activity of anticancer drugs, as has been shown in preclinical studies. The aim of this thesis was to explore the combined use of TRAIL-receptor targeting therapies with the anticancer drug bortezomib in preclinical models of non-small cell lung cancer. It was found that the combination strongly induces apoptosis. Bortezomib could overcome tumour cell preferences for TRAIL-receptor1 or TRAIL-receptor2 apoptosis and enhance apoptosis induced via both receptors in the cancer cells. Examination of the underlying mechanisms revealed that bortezomib could sensitize TRAIL-induced apoptosis at the level of DISC (at the membrane) as well as at the level of the mitochondria (intracellular). Bortezomib had an effect on TRAIL-receptor endocytosis, although its functionality remains unknown.