|dc.identifier.citation||Dermit, M. 2017. Understanding the biochemical alterations in cancer cells chronically treated with PI3K/mTOR inhibitors. Queen Mary University of London||en_US
|dc.description.abstract||The PI3K/mTOR signalling pathway plays a major role in biology and disease. Therefore, effective
inhibitors that target proteins of this pathway have been developed. However, acquired resistance of
cancer cells is a prevalent phenomenon that limits the durable response of these compounds.
It is becoming apparent that experimental approaches for comprehensive biochemical analysis
contribute to understand the complex mechanisms that confer drug resistance, and advances in largescale
technologies including genomic sequencing and proteomics allow unprecedented molecular
coverage without being biased for specific genes/cellular pathways.
Initially, the phenotypic response of sensitive and resistant cells to the absence or presence of a
PI3K inhibitor (PI3Ki), as well as other kinases, was examined. This study revealed that PI3Ki-resistant
cells experience extensive phenotypic changes upon withdrawal of the PI3Ki from the culture media.
The regulation of the proteome and phosphoproteome of sensitive and PI3Ki-resistant cells grown
with or without the PI3Ki was analysed by shotgun mass spectrometry-based label-free quantitative
technology. This analysis demonstrated that the proteomes and phosphoproteomes of drug-resistant
cells are remodelled conditional to the presence of PI3Ki, and that the levels of enzymes with
metabolic roles are modulated in resistant cells. Functional analysis of the metabolism of cells capable
to survive in absence of PI3K/mTOR activity demonstrated that the bioenergetic activity of these cells
is contingent on the presence of the selection drug.
The complete set of protein-coding regions of the genome (exome) of sensitive and PI3Ki-resistant
cells was then sequenced. This study unveiled common alterations in exome regions across PI3Kiresistant
cell lines, as well as a degree of genomic heterogeneity between them.
Lastly, the impact of lactic acid, a metabolic product, on a defined signalling network of the MCF7
breast cancer cell line was analysed. This study described the capacity of this metabolite to change
the activity of signalling network branches.||en_US
|dc.publisher||Queen Mary University of London||en_US
|dc.rights||The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author||
|dc.subject||Barts Cancer Institute||en_US
|dc.subject||PI3K/mTOR signalling pathway||en_US
|dc.title||Understanding the biochemical alterations in cancer cells chronically treated with PI3K/mTOR inhibitors||en_US