1011 - THE ROLE OF MUTANT P53 IN TUMOR DEVELOPMENT AND THE RESPONSE OF MALIGNANT CELLS TO ANTI-CANCER THERAPEUTICS

Abstract

p53 is a highly potent tumour suppressor that acts through activation of several biological processes, including apoptotic cell death, cell growth arrest and cell senescence. In accordance with its critical role in tumour suppression, the p53 gene is the most frequently mutated gene in human cancers. Mutant p53 cancers are usually relatively resistant to chemotherapeutic drugs and such patients therefore often have a poor prognosis. Despite several decades of research into the functions of wild-type (wt) p53 in normal cells and mutant p53 in tumour cells, we still do not have a clear understanding of how mutations in p53 contribute to the development and sustained growth of cancers. There is evidence to support the notion that mutant p53 acts only to blocks wt p53 tumour suppressor functions (dominant negative effect; DNE) but there are also reports that mutant p53 has de novogain-of-function properties that additionally promote tumour growth. Of critical importance is the question of whether mutant p53 contributes to the sustained growth of established tumours, thereby validating whether abrogating its expression would be a promising therapeutic approach. Clarification of this point has profound implications for the future development and clinical success of cancer drugs that aim to directly target and degrade mutant p53. We have investigated the role of mutant p53 in aggressive MYC-driven lymphomas, focusing on how it functions during tumour development and also the response to conventional and targeted cancer therapeutics.