Pathology - Theses

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The role of MDM2 and CDK4 in well differentiated liposarcoma

CONYERS, RACHEL ( 2015)

Transformation of normal cells to cancer cells is tightly linked to fundamental changes in cell cycle regulation. In addition, oncogenes can aberrantly enhance cell proliferation. Two genes; Cyclin dependent kinase-4 (CDK4) and Murine double minute 2 (MDM2) are amplified and overexpressed in over 90% of well differentiated liposarcomas. Their role in cell cycle control, and regulation of tumour suppressor p53 respectively, strongly suggesting that deregulation of these genes confers some selective advantage to this tumour. To elucidate the role of these genes in the development and progression of liposarcoma I have used transgenic mouse models and in vitro assays. Given the recent development of novel CDK4 inhibitors, I have tested several CDK4 inhibitors (sc-203873, sc-203874, NPCD, PD 0332991) on liposarcoma cell lines (449B, T1000, 778, GOT3) to determine sensitivity to inhibition, cell cycle arrest and downstream effects of inhibition. PD033991 was found to be the most selective and sensitive CDK4 inhibitor and, as such, was used in a siRNA screen of the genome to identify co-modifiers of CDK4 inhibition. A total of 13 genes were identified that produced a resistance phenotype in the context of CDK4 inhibition. Two of these genes; Arrestin, beta 2 (ARRB2) and Dysferlin (DYSF) demonstrated a reproducible resistance phenotype in a series of functional validation studies.