Mechanisms of non-apoptotic TRAIL signalling in NSCLC

Lung cancer is one of the most common cancers worldwide and is responsible for most cancer-related deaths. 85% of lung cancer patients have non-small cell lung cancer (NSCLC). Despite the successful development of targeted anti-cancer therapies for NSCLC, the prognosis often remains poor. Novel therapies are needed and tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor 1(R1) and TRAIL-R2 are promising therapeutic targets, as they selectively induce cell death (apoptosis) in tumour cells. Unfortunately, NSCLC cells can be resistant to TRAIL and treatment can result in tumour cell proliferation and metastasis through activation of non-canonical molecular mechanisms that are not yet fully understood. Previous research by our laboratory demonstrated that the Src kinase protein plays an important role in non-canonical TRAIL signalling. In this thesis, we further investigated the role of Src in this process, which may lead to improved therapeutic TRAIL treatment. We found that TRAIL-dependent Src activation does not result in TRAIL resistance, but influences the secretion of immune cell regulatory cytokines. Furthermore, we identified various Src binding proteins that may contribute to the undesired effects of TRAIL treatment. Additionally, we showed that 3D cultured NSCLC cells respond similarly to TRAIL treatment as the normally used 2D cultures. A new synthetic matrix was found to be suitable for use in 3D culturing. The role of Src in NSCLC in TRAIL treatment was found to be complex and to have both cell intrinsic and extrinsic effects. Further research is needed to elucidate the exact role of Src in TRAIL resistance.