Mechanisms of TRAIL-resistance: novel targets to enhance TRAIL sensitization for cancer therapy

TRAIL has been shown to target tumor cells but not healthy cells in vitro. In addition, clinical studies have revealed that recombinant human TRAIL is well tolerated in patients. Taken together, the safety of treatment and targeted apoptosis in human bodies render TRAIL a promising anti-tumor therapeutic. Besides inducing this apoptotic signaling pathway, TRAIL can activate non-canonical kinase pathways through the same death receptors. In this thesis, we unraveled molecular mechanisms controlling TRAIL sensitivity in tumor cells using DR4- and DR5- specific TRAIL variants (Chapter 2 and 3). Moreover, we used combined treatment with epigenetic drugs to overcome TRAIL resistance in tumor cells (Chapter 5 and 6). In Chapter 2 , we generated FUT3 or FUT6 overexpressed cell lines to investigate their sensitivities to TRAIL. Our data show that DR5-sensitivity is completely restored in FUT3 or FUT6 overexpressed cells. In Chapter 3, we firstly showed that conditioned medium (CM) derived from cancer cells inhibits TRAIL-mediated cell death. In addition, we observed only DR5 but not DR4 in CM. In Chapter 4. We summarized strategies for combination therapy to improve TRAIL sensitivity by interfering with aberrant histone modifications using inhibitors. In Chapter 5, we found that RGFP966, a HDAC3-specific inhibitor, or PCI34051, a HDAC8-specific inhibitor, largely improve TRAIL sensitivity in combination with agonistic receptor-specific. TRAIL variants. In Chapter 6, we showed that the A485-TRAIL combination synergistically increases cell death and decreases the volume of 3D spheroids of EGFR-TKI resistant cells.