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Title: Overcoming mitochondrial apoptosis block in non small cell lung cancer for effective therapy
Author: Paul, David Ian
ISNI:       0000 0004 2742 5236
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2012
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Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality. The majority of patients present with advanced disease where platinum based systemic therapy forms the mainstay of treatment but is ) associated with high failure rates. Defective apoptosis underpins drug resistance. Mitochondrial apoptosis is regulated by the BCL-2 family proteins, BAX and BAK. Loss of these proteins confers multidrug apoptosis resistance, however their requirement for the action of cisplatin is unclear. Altered expression of BAX and BAK is frequent in NSCLC. Results presented show that BAX and BAK gene expression is positively correlated suggesting BAX and BAK double negativity is a common phenotype in NSClC. BAXBAK double negativity was modelled in the H460 and H1299 NSCLC cell lines. Unexpectedly, in H460 shBAXBAK models we demonstrate redundancy of core apoptosis signalling in relation to cisplatin through its ability to activate the death receptor pathway. This pathway has de novo block in H1299 cells such that H1299 shBAXBAK cells fail to induce apoptosis in response to cisplatin. This pathway is abrogated in cisplatin ) resistance, whereas sensitivity to death receptor agonism is conserved. Synthetic lethality, through targeting BRCA1/2 mutated tumours with PARP inhibitors, is a promising therapeutic strategy. Decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. Results presented demonstrate that silencing of BRCA 1 expression sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block. Furthermore, we demonstrate that BRCA 1 inhibition cannot override platinum resistance, but can still sensitize to PARP inhibition. 11-19% of NSCLC patients have absent BRCA1 protein expression. This molecular subgroup could be effectively targeted by PARP inhibitors. As a result of this work, the PIN study (PARP inhibitors in NSCLC) has been funded to assess the effectiveness of this therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available