AbstractThe development of resistance to carboplatin and paclitaxel chemotherapy remains one of the major hurdles in the treatment of epithelial ovarian cancer (EOC). The benefit of paclitaxel, in contrast to carboplatin, is more variable and the drug can be associated with significant side-effects. The identification of a protein biomarker that predicts paclitaxel response and investigation into the mechanisms underlying this may allow more personalised treatment.
Bioinformatic analysis of reverse phase protein array (RPPA) expression data from resistant and sensitive cohorts found a number of possible proteins with differential expression in resistant patients. These were taken forward for in vitro investigation, where the only protein found to influence paclitaxel response was the oncoprotein c-Myc.
c-Myc is an important transcription factor amplified in around 30% of EOC. Cell viability assays found the loss of c-Myc by siRNA knockdown increased resistance to paclitaxel in a cell line panel that included the ovarian cell line OVCAR4 and the cervical cancer cell line HeLa.
Live cell imaging revealed cells with loss of c-Myc were more likely to evade mitotic arrest and slip into G1 having failed to undergo cell division. Investigation of the mitotic timing and cell death pathways, which combine to determine the fate of mitotically arrested cells, suggested that this phenotype is likely due to altered apoptotic pathways, including the Bcl2 family proteins, as opposed to effects on mitotic timing.
Expression of c-Myc was found to be altered over the course of a paclitaxel mitotic arrest, with c-Myc undergoing proteasomal dependent degradation. This is a novel finding, along with the mitotic phosphorylation of c-Myc at Serine 62 and Threonine 58 which may regulate the stability of c-Myc during mitosis.
Further translational work is required to validate an association between reduced c-Myc expression and paclitaxel resistance in clinical samples, but the work presented in this thesis suggests this investigation is warranted. The ability to predict those patients who are resistant to paclitaxel would allow more individualised treatment and improve quality of life by allowing the avoidance of an ineffective toxic treatment.
|Date of Award||2021|
|Sponsors||Cancer Research UK|
|Supervisor||Gillian Smith (Supervisor), Russell Petty (Supervisor) & Paul Clarke (Supervisor)|
- Ovarian Cancer
- paclitaxel resistance