Targeting the p53 signaling pathway in cancer therapy the promises, challenges and perils

Introduction: Research over the past three decades has identified p53 as a multi-functional transcription factor. p53 influences myriad, highly diverse cellular processes, and represents one of the most important and extensively studied tumor suppressors. Activated by various stresses, p53 blocks cancer progression by provoking transient or permanent growth arrest, by enabling DNA repair, or by advancing cellular death programs. This anti-cancer activity profile, together with genomic and mutational analyses documenting inactivation of p53 in more than 50% of human cancers, motivated drug development efforts to (re-) activate p53 in established tumors. Areas covered: The complexities of p53 signaling in cancer are summarized, including current strategies and challenges to restore p53's tumor suppressive function in established tumors, to inactivate p53 inhibitors, and to restore wild type function of p53 mutant proteins. Expert opinion: p53 represents an attractive target for the development of anti-cancer therapies. Whether p53 is 'druggable', however, remains an area of active research and discussion, as p53 has pro-survival functions and chronic p53 activation accelerates aging, which may compromise the long-term homeostasis of an organism. The complex biology and dual functions of p53 in cancer prevention and age-related cellular responses pose significant challenges to the development of p53-targeting cancer therapies.