Targeting mutant p53 for cancer therapy: direct and indirect strategies.

TP53 is a critical tumor-suppressor gene that is mutated in more than half of all human cancers. Mutations in TP53 not only impair its antitumor activity, but also confer mutant p53 protein oncogenic properties. The p53-targeted therapy approach began with the identification of compounds capable of restoring/reactivating wild-type p53 functions or eliminating mutant p53. Treatments that directly target mutant p53 are extremely structure and drug-species-dependent. Due to the mutation of wild-type p53, multiple survival pathways that are normally maintained by wild-type p53 are disrupted, necessitating the activation of compensatory genes or pathways to promote cancer cell survival. Additionally, because the oncogenic functions of mutant p53 contribute to cancer proliferation and metastasis, targeting the signaling pathways altered by p53 mutation appears to be an attractive strategy. Synthetic lethality implies that while disruption of either gene alone is permissible among two genes with synthetic lethal interactions, complete disruption of both genes results in cell death. Thus, rather than directly targeting p53, exploiting mutant p53 synthetic lethal genes may provide additional therapeutic benefits. Additionally, research progress on the functions of noncoding RNAs has made it clear that disrupting noncoding RNA networks has a favorable antitumor effect, supporting the hypothesis that targeting noncoding RNAs may have potential synthetic lethal effects in cancers with p53 mutations. The purpose of this review is to discuss treatments for cancers with mutant p53 that focus on directly targeting mutant p53, restoring wild-type functions, and exploiting synthetic lethal interactions with mutant p53. Additionally, the possibility of noncoding RNAs acting as synthetic lethal targets for mutant p53 will be discussed.

Wild type p53 function in p53Y220C mutant harboring cells by treatment with Ashwagandha derived anticancer withanolides: bioinformatics and experimental evidence.

BACKGROUND: Tumor suppressor p53 protein is frequently mutated in a large majority of cancers. These mutations induce local or global changes in protein structure thereby affecting its binding to DNA. The structural differences between the wild type and mutant p53 thus provide an opportunity to selectively target mutated p53 harboring cancer cells. Restoration of wild type p53 activity in mutants using small molecules that can revert the structural changes have been considered for cancer therapeutics. METHODS: We used bioinformatics and molecular docking tools to investigate the structural changes between the wild type and mutant p53 proteins (p53V143A, p53R249S, p53R273H and p53Y220C) and explored the therapeutic potential of Withaferin A and Withanone for restoration of wild type p53 function in cancer cells. Cancer cells harboring the specific mutant p53 proteins were used for molecular assays to determine the mutant or wild type p53 functions. RESULTS: We found that p53V143A mutation does not show any significant structural changes and was also refractory to the binding of withanolides. p53R249S mutation critically disturbed the H-bond network and destabilized the DNA binding site. However, withanolides did not show any selective binding to either this mutant or other similar variants. p53Y220C mutation created a cavity near the site of mutation with local loss of hydrophobicity and water network, leading to functionally inactive conformation. Mutated structure could accommodate withanolides suggesting their conformational selectivity to target p53Y220C mutant. Using human cell lines containing specific p53 mutant proteins, we demonstrated that Withaferin A, Withanone and the extract rich in these withanolides caused restoration of wild type p53 function in mutant p53Y220C cells. This was associated with induction of p21WAF-1-mediated growth arrest/apoptosis. CONCLUSION: The study suggested that withanolides may serve as highly potent anticancer compounds for treatment of cancers harboring a p53Y220C mutation.

Synergistic and additive effect of retinoic acid in circumventing resistance to p53 restoration.

TP53 mutations occur in ∼50% of all human tumors, with increased frequency in aggressive cancers that are notoriously difficult to treat. Additionally, p53 missense mutations are remarkably predictive of refractoriness to chemo/radiotherapy in various malignancies. These observations have led to the development of mutant p53-targeting agents that restore p53 function. An important unknown is which p53-mutant tumors will respond to p53 reactivation-based therapies. Here, we found a heterogeneous impact on therapeutic response to p53 restoration, suggesting that it will unlikely be effective as a monotherapy. Through gene expression profiling of p53R172H -mutant lymphomas, we identified retinoic acid receptor gamma (RARγ) as an actionable target and demonstrated that pharmacological activation of RARγ with a synthetic retinoid sensitizes resistant p53-mutant lymphomas to p53 restoration, while additively improving outcome and survival in inherently sensitive tumors.

Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity.

Lung adenocarcinoma accounts for ∼40% of lung cancers, the leading cause of cancer-related death worldwide, and current therapies provide only limited survival benefit. Approximately half of lung adenocarcinomas harbor mutations in TP53 (p53), making these mutants appealing targets for lung cancer therapy. As mutant p53 remains untargetable, mutant p53-dependent phenotypes represent alternative targeting opportunities, but the prevalence and therapeutic relevance of such effects (gain of function and dominant-negative activity) in lung adenocarcinoma are unclear. Through transcriptional and functional analysis of murine KrasG12D -p53null , -p53R172H (conformational), and -p53R270H (contact) mutant lung tumors, we identified genotype-independent and genotype-dependent therapeutic sensitivities. Unexpectedly, we found that wild-type p53 exerts a dominant tumor-suppressive effect on mutant tumors, as all genotypes were similarly sensitive to its restoration in vivo. These data show that the potential of p53 targeted therapies is comparable across all p53-deficient genotypes and may explain the high incidence of p53 loss of heterozygosity in mutant tumors. In contrast, mutant p53 gain of function and their associated vulnerabilities can vary according to mutation type. Notably, we identified a p53R270H -specific sensitivity to simvastatin in lung tumors, and the transcriptional signature that underlies this sensitivity was also present in human lung tumors, indicating that this therapeutic approach may be clinically relevant.