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Title: Sensitisation to TRAIL-induced apoptosis by targeted inhibition of kinases
Author: Papenfuss, Kerstin
ISNI:       0000 0004 2706 272X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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The tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cell lines but not in normal cells. This property of TRAIL led to its development as a novel cancer drug. However, most primary tumour cells are TRAIL-resistant, yet, they can be sensitised by combining TRAIL with other cancer drugs. Kinase inhibitors have emerged as a new class of cancer drugs with high therapeutic potential and cancer cell specificity. The aim of this thesis was to determine the mechanism of TRAIL apoptosis sensitisation by inhibition of certain kinases that are specifically and aberrantly activated in cancer cells. When studying the TRAIL-induced phosphorylation of Bid it was discovered in this thesis that this phosphorylation was independent of ATM which has previously been described to phosphorylate Bid at this specific site. Remarkably, the ATM inhibitor KU-55933 used in this context was able to further sensitise HeLa cells to TRAIL-induced apoptosis and could break TRAIL resistance of the colon carcinoma cell line DLD1. As the combination of TRAIL and KU-55933 might represent a promising treatment option for cancer therapy this study focused on investigating the molecular mechanism that leads to TRAIL sensitisation by KU-55933. Surprisingly, TRAIL sensitisation by KU-55933 was independent of specific inhibition of ATM and, instead, achieved by inhibition of the phosphoinositide 3-kinase (PI3K) p110α isoform. Aberrant activation of PI3K α is a frequent tumour-specific alteration in various types of cancer including breast and colon carcinoma. It could be demonstrated that TRAIL apoptosis sensitisation of TRAIL-resistant DLD1 colon carcinoma cells by KU-55933 or PIK75, a specific inhibitor for p110α, required concomitant down-regulation of the cellular FLICE-inhibitory protein (cFLIP) and the X-linked Inhibitor of Apoptosis Protein (XIAP). Whilst suppression of cFLIP enhanced caspase-8 activation at the TRAIL death-inducing signalling complex (DISC), resulting in first cleavage of caspase-3, loss of XIAP enabled further cleavage and full activation of caspase-3. These results suggest that the combination of TRAIL or other TRAIL receptor agonists with inhibitors of PI3Kα may be an effective new strategy in cancer treatment capable of overcoming therapy resistance.
Supervisor: Walczak, Henning Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral