Targeting mutant p53 for cancer therapy

p53 tumor suppressor protein serves as a major barrier against cancer; consequently, mutations in the TP53 gene, encoding p53, are the most frequent single genetic alteration in human cancer, occurring in about half of all individual cancer cases [1]. Besides abrogating the tumor suppressive effects of the wild type (WT) p53 protein, many of the TP53 mutations endow the mutant p53 protein with new oncogenic gain-of-function activities, which actively promote a variety of features characteristic of aggressive tumors, such as increased migratory and invasive capacities and increased resistance to many types of anti-cancer therapy agents [1]. This pertains particularly to tumors that carry single amino acid substitutions (missense mutations) within p53's DNA binding domain (DBD), and display abundant accumulation of the mutant p53 protein within the tumor cells [1]. In tumors that retain non-mutated TP53 genes, the tumor suppressive effects of the remaining WTp53 are also often compromised, owing to genetic and epigenetic alterations that occur during cancer progression [1]. Altogether, the normal functionality of p53 is thus abrogated in the vast majority of human tumors. This realization has led to extensive attempts to restore full p53 functionality in cancer cells, as a novel cancer therapy strategy [1, 2]. However, these attempts have been seriously hampered by the fact that p53 has no known enzymatic activities, and rather operates primarily as a sequence-specific transcription factor. Furthermore, restoring the activity of a defective tumor suppressor protein is vastly more difficult than abrogating the activity of a hyperactive oncoprotein. Nevertheless, significant advances have been achieved in recent years, and hopes for the introduction of p53-based novel cancer therapies into the clinic are becoming increasingly supported by evidence. In principle, attempts to develop such therapies have taken 3 main approaches: (1) Introduction of WTp53, mainly via viral transduction (" gene therapy "), into tumors that have sustained TP53 mutations; (2) enhancement of the functionality of the endogenous WTp53 in tumors that have retained a non-mutated TP53 gene, mainly be disrupting the interaction of the WTp53 protein with its major negative regulator MDM2; and (3) " correction " of the mutant p53 protein in tumors that have sustained Editorial TP53 missense mutations, thereby restoring its ability to perform the tumor suppressive activities of WTp53 [1, 2]. The latter approach, namely the " re-education " of mutant p53, is particularly appealing. First of all, it can simultaneously reinstate WTp53 tumor suppressive activity together with abrogating …