Oncogene-induced senescence and the role of p53 in BRAFV600E melanoma

Abstract

This thesis examines the concept that human naevi are permanently arrested via the oncogene-induced senescence and investigates the role of p53 function in melanocyte responses to oncogenic mitogen-activated protein kinase (MAPK) pathway activity. We demonstrate that a panel of common markers of senescence are collectively unable to distinguish melanocytes from naevi and melanoma, questioning the proposition that naevi are composed of senescent cells. We also examined the signalling pathways involved in the oncogene-induced senescence of cultured melanocytes and found that levels of p53 rapidly diminished in response to ectopic BRAFV600E, an activator of MAPK activity and major oncogenic driver of melanoma. Importantly, we confirmed that p53-downregulation is transcriptional and we identified potential p53 regulators via whole-genome microarray analyses. We next sought to establish whether p53 is upregulated in response to MAPK pathway inhibition (a first-line therapy for patients with BRAFV600-mutant advanced melanoma). Initially, we analysed isogenic, colorectal cancer cell models and found that p53-loss diminished the sensitivity of these cancer cells to the MAPK inhibitor, trametinib. Although, sensitivity to trametinib was not significantly altered by p53-loss in the melanoma cells, our data suggest that melanoma cells do not potently induce p53 accumulation in response to MAPK inhibition.