- Title
- Identifying novel therapeutic targets for the treatment of Acute Myeloid Leukaemia
- Creator
- Murray, Heather
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2020
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Acute Myeloid Leukaemia (AML) is the most common and aggressive form of acute leukaemia, with a 5-year survival rate of just 24%. Activating mutations in the receptor tyrosine kinase FLT3 are the most common driver mutations in AML, occurring in 25-30% of patients. FLT3 inhibitors show clinical benefit in FLT3-mutant AML patients when used in combination with chemotherapy. However, 5-year survival is just over 50% with this regime, therefore improved therapies are still needed. To address this, a better understanding of the oncogenic pathways activated downstream of FLT3 in AML patients is required. In this thesis, analysis of quantitative label-based phosphoproteomics performed on primary blasts from 4 FLT3-mutant and 3 FLT3-wildtype AML patients was conducted. Comparison of differentially expressed phosphoproteins in FLT3-mutant compared to FLT3-wildtype patients revealed dysregulation of DNA repair pathways. Specifically, FLT3-mutant samples displayed increased phosphorylation of proteins within the Non-Homologous End Joining (NHEJ) DNA double strand break repair pathway, indicating NHEJ pathway activation. Accordingly, FLT3-mutant AML cell lines were sensitive to inhibition of the NHEJ core kinase, DNA-PK. Inhibition of DNA-PK combined with FLT3 inhibition led to synergistic induction of cell death, in FLT3-mutant cell lines and FLT3-mutant primary AML patient samples ex vivo. Furthermore, DNA-PK inhibitor therapy combined with FLT3 inhibition significantly prolonged survival compared to either monotherapy in an orthotopic human xenograft mouse model of AML. Further phosphoproteomic data analysis revealed additional signalling pathways associated with other common AML molecular subtypes, which may also be therapeutically targetable. In conclusion, phosphoproteomic analysis is a powerful approach for the identification of activated, druggable signalling pathways. The work contained in this thesis has identified DNA-PK as a novel therapeutic target for FLT3-mutant AML, and combined inhibition of DNA-PK and FLT3 shows great promise for improved treatment of FLT3-mutant AML
- Subject
- AML; FLT3; phosphoproteomics; DNA repair
- Identifier
- http://hdl.handle.net/1959.13/1411185
- Identifier
- uon:36309
- Rights
- Copyright 2020 Heather Murray
- Language
- eng
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 11 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 333 KB | Adobe Acrobat PDF | View Details Download |