Kumar, Neelam; (2018) Mechanisms of TRAIL resistance. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Malignant pleural mesothelioma (MPM) is a devastating disease for which limited effective therapies are currently available. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and other death receptor (DR) agonists are pro-apoptotic agents that trigger the extrinsic apoptotic pathway selectively in cancer cells. Previous work has shown that supports that loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1) augments sensitivity to recombinant TRAIL (rTRAIL) in MPM cells. This study shows that BAP1 is a candidate biomarker for rTRAIL sensitivity in cell line, early passage culture and tumour explant models of MPM. In addition, BAP1 is a potential biomarker for sensitivity to other DR agonists and for additional cancer types with BAP1 mutations. I have also identified other novel candidate biomarkers for DR agonist sensitivity, notably ASXL1/2, through exploration of the mechanism underlying the BAP1-rTRAIL association. I present data supporting the clinical relevance and utility of the BAP1-TRAIL association. I have shown that loss of BAP1 function occurs in a significant proportion of MPM tumours in the UK and that loss of BAP1 function augments sensitivity to TRAIL in primary tumour tissue. I describe in vitro data supporting the hypothesis that loss of BAP1 function augments sensitivity to rTRAIL in MPM. I have shown that loss of BAP1 function augments sensitivity to other DR agonists and that BAP1 can act as a biomarker for DR agonist sensitivity in other cancers with BAP1 mutations. Finally, I explore the mechanism underlying the BAP1-TRAIL association. I present data supporting the notion that BAP1 binds to the ASXL1/2 proteins to form the polycomb repressor deubiquitinase complex which underlies BAP1-induced TRAIL resistance. Loss of this function results in a change in the expression of proteins of the extrinsic apoptotic pathway, which may favour apoptosis upon DR agonist binding.

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