p53 as a therapeutic target: unresolved issues on the road to cancer therapy targeting mutant p53

As a tumor suppressor, p53 has a central role in oncogenesis: it inhibits the growth of abnormal cells and thus prevents cancer development. The frequent occurrence of p53 mutations in human cancer and its role as "guardian of the genome" has led to numerous investigations evaluating its role as a potential therapeutic target in terms of restoring wild type (wt) p53 and thereby either reverting the malignant phenotype or enhancing drug sensitivity. A critical evaluation of the available data suggests that following the restoration of wt p53 growth inhibition is an attainable goal, although induction of apoptosis would be more desirable. As for attempts to enhance drug sensitivity, the evidence suggest that this too can be accomplished, but how best to accomplish it remains to be explored. To properly evaluate these strategies, one must consider the known and putative roles of p53. Research conducted in the last decade has firmly established the importance of p53 in mediating the cell cycle arrest that occurs following DNA damage. However, during this same time, the role of p53 in mediating apoptosis has become increasingly less clear, even as the number of putative pro-apoptotic proteins transactivated by p53 has increased. Similarly unclear is how p53 makes a choice between cell cycle arrest or apoptosis, raising the possibility that p53 alone is not responsible for this crucial decision. Despite the existence of several crucial unresolved issues, strategies attempting to enhance the expression of the wt p53 phenotype in cancer cells deserve further investigation. Although the importance of p53 in maintaining an established malignant phenotype as well as its role in apoptosis and chemotherapy-induced cytotoxicity are far from settled, a subset of cancers may respond to these strategies.