PhD ceremony Ms. K. Azijli: TRAIL-induced kinases activation and apoptosis: towards improved death receptor targeted therapy for lung cancer

PhD ceremony: Ms. K. Azijli, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: TRAIL-induced kinases activation and apoptosis: towards improved death receptor targeted therapy for lung cancer

Promotor(s): prof. F.A.E. Kruyt, prof. G.J. Peters, prof. S. de Jong

Faculty: Medical Sciences

Lung cancer is one of the deadliest diseases amongst the different types of cancer and the incidence is expected to rise globally. The current treatment of NSCLC patients has reached a plateau since efficacy of therapy is limited by resistance to conventional chemo- and radiotherapy. New therapies are therefore urgently needed to improve lung cancer survival. Targeting the apoptotic machinery by activating Tumor Necrosis Factor-related apoptosis-inducing ligand (TRAIL) receptors represents a novel approach and aims to selectively kill cancer cells by apoptosis activation while sparing normal cells. In this thesis part of the work was dedicated to examine the possible counterproductive effects of TRAIL stimulation in NSCLC and to unravel underlying mechanisms of non-canonical kinases signaling. However, the differential sensitivity for apoptosis induction and even pro-tumorigenic effects in TRAIL resistant tumor cells, requires a better understanding of the mechanisms that regulate TRAIL activity. Regardless of the more detailed molecular causes of the dichotomy in TRAIL signaling, the combined use with standard anti-cancer drugs generally results in sensitization to TRAIL-induced apoptosis. Thus, possible unwanted effects of TRAIL treatment can be overcome by combination treatments, such as the ones we presented in this thesis, TFT and Hsp90 inhibitors. Elucidation of the molecular switches that determine the settings of the TRAIL pathway will help to develop targeted strategies to make the tumor cells apoptosis prone. Another challenge for the future is to identify biomarkers that allow the preselection of patients and determination of optimal TRAIL combination strategies in order to maximize therapeutic benefit.