Mechanisms of non-apoptotic TRAIL signalling in NSCLC
General introduction Non-small cell lung cancer Cancer is currently the second cause of death after cardiovascular diseases worldwide. However, it is predicted to become the primary cause of death in the near future 1 . It is expected that globally the burden of cancer rises to 18.1 million new cases and 9.6 million deaths 1 . Lung cancer is the major cause of total cancer related deaths (18.4%) and has a 5 year survival rate of only 18.3% 1,2 . Non-small cell lung cancer (NSCLC) is the most
... valent type, accounting for 85% of lung cancer cases, of which lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LSCC) are the most prevailing subtypes 3 . The remaining 15% of the lung cancers consist of small cell lung cancer (SCLC). Current treatment options depend on the stage and genetic profile of the cancer and include surgery, radiotherapy, chemotherapy, targeted therapies and/or immune checkpoint inhibitors. Intensive research to biological drivers of NSCLC and the technological developments during the past decade, including next generation sequencing and the different -omics platforms, have resulted in the discovery and application of targeted therapies. Numerous activating mutations in oncogenic drivers have been found in NSCLC, of which KRAS (25%), epidermal growth factor receptor (EGFR) (17%) and anaplastic lymphoma kinase (ALK) (7%) are the three most frequent occurring aberrations 4 . Targeted therapies for patient with mutant EGFR and ALK are successfully applied  . For other genetic abnormalities new strategies are being developed, of which some are currently under investigation in clinical trials 4 . In spite of the successful application of targeted therapies the overall survival rate of lung cancer remains low compared to other cancer types 2 . Apoptotic TRAIL signalling An interesting therapeutic biological agent for various tumours, including NSCLC, is the tumour-necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL). TRAIL induces selective apoptosis in tumour cells by pro-apoptotic/canonical signalling that is induced via TRAIL-receptor 1 (-R1/DR4) and/or TRAIL-R2 (DR5), but leaves normal cells unharmed  . Three other TRAIL receptors have been identified: the TRAIL-R3 (DcR1), TRAIL-R4 (DcR2) and the soluble Osteoprotegerin (OPG). These three receptors fail to trigger apoptotic responses and are believed to function as decoy receptors that sequester TRAIL, although TRAIL-R4 was reported to modulate T cell cytotoxicity towards cancer cells 11,12 . However, the exact function(s) of the decoy receptors need to be further explored 13 . Activation of TRAIL-R1 and TRAIL-R2 by TRAIL induces homo-or heterotrimerization and subsequent recruitment of Fas-Associated protein with Death Domain (FADD) and pro-caspase 8 at the intracellular death effector domains (DED) of the receptors (Fig. 1 ). At that instant Caspase 8 is cleaved and activated, and triggers the so-called death receptor, or extrinsic apoptotic pathway, by cleaving downstream substrates including 16 Chapter 1 9. Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family.