The FMS-like tyrosine kinase 3- internal tandem duplication (FLT3/ITD) aberration is common in acute myeloid leukemia (AML) and associated with poor patient outcome. Inhibitors targeting FLT3/ITD are in development, but clinical responses are transient. This project focussed on elucidating molecular signalling consequences of FLT3/ITD inhibition, to identify rational drug combinations for future development. A Multicolour Phospho Flow Cytometry (MPFC) assay was developed to assess signalling events downstream of FLT3/ITD in primary patient samples, focusing on alterations in ERK, STAT5, Akt, and S6. STAT5 signalling appeared to be important exclusively in FLT3/ITD samples. MPFC accurately predicted the presence of FLT3/ITD, inhibitor sensitivity and the initial positive clinical response of a trial patient receiving a FLT3/ITD inhibitor. PI3K pathway upregulation was observed in a Sorafenib-resistant FLT3/ITD cell line established to study resistance mechanisms of FLT3 inhibition. Further, combination FLT3 and PI3K inhibition demonstrated synergy, suggesting potential clinical relevance to this therapeutic strategy.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/30545 |
| Date | 06 December 2011 |
| Creators | Chen, Hsiao-Wei Tina |
| Contributors | Hedley, David |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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