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.
The tumor-suppressor p53, encoded by the TP53 gene (or Trp53 in mice), is critical for normal cell growth and tumor prevention [1, 2]. Generally, the p53 protein is kept at a low level in normal tissue by its negative regulator, mouse double minute 2/X (MDM2/X) [3]. Numerous endogenous and exogenous stressors can activate p53, triggering it to further regulate a series of cellular responses necessary for homeostasis maintenance (Fig. 1) [4]. The activation of p53 in response to multiple stresses is critical for normal cells to survive and protect themselves from tumorigenesis. However, TP53 is frequently mutated in most human cancers, resulting in the loss of functions (LOFs) necessary for tumor suppression and even the gain of functions (GOFs) necessary for tumor growth [5, 6]. The most common p53 mutation is the missense mutation in the DNA-binding domain (DBD), which affects only one amino acid in the p53 protein but has a significant effect on the protein's function [7]. Tumors harbor p53 mutations frequently progress more rapidly, have a poor response to anticancer therapy, and have a poor prognosis [6, 8, 9]. Therefore, targeting p53 for cancer therapy is an attractive strategy.
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Depending on the p53 status, p53 treatments may include preventing the degradation of wild-type p53 (wtp53), suppressing mutant p53 (mutp53), or restoring the wild-type functions of mutp53 [10, 11]. Agents that protect wtp53 primarily act by interfering with the interactions of p53 and its negative regulators, most notably MDM2, to prevent subsequent ubiquitination [12]. Increased wtp53 levels are sufficient to induce tumor-suppressive responses [13]. Different strategies for restoring p53 functions have been developed based on the variety of mutp53 protein structures as well as their specific functional deficiencies [14]. Additionally, p53 GOF mutations confer oncogenic properties on cancer cells, and thus, targeting these specific mutations may inhibit cancer cell proliferation [15]. Despite their relative advantages, these treatments have a very limited effect due to the prevalence of mutp53 variants. Thus, a superior strategy that specifically targets the majority of mutant p53 can result in greater therapeutic benefit for patients.
While intact TP53 is present in some cancers, the tumor suppressor is always inhibited via a variety of mechanisms. MDM2 is the major negative regulator of p53, which prevents p53 from entering the nucleus, inhibits its DNA binding, and promotes p53 proteasomal degradation [29, 30]. Genetic amplification is the most frequent genomic alteration of MDM2, which was first found in soft-tissue sarcoma [31]. It was discovered that amplification and overexpression of MDM2 were mutually exclusive with p53 mutation [32]. Oliner et al. discovered that MDM2 overexpression involved intact p53 across cancer types in a study using The Cancer Genome Atlas (TCGA) database [33]. Thus, inhibiting MDMs in cancers with wtp53 is an intriguing therapeutic strategy that has been successfully applied in clinical settings (Table 1). Since the discovery of a class of cis-imidazoline analogues known as nutlins that inhibit p53-MDM2 binding, MDM2 inhibitors have been extensively studied as a targeted treatment for patients with wtp53 [12, 34]. Nutlin-3a, a preclinical drug, inhibits tumor growth by reactivating wild-type p53, whether used alone or in combination with other therapies [35,36,37]. Due to the promising results of in vitro studies, clinical trials were conducted to assess the efficacy and safety of the derivative of nutlins, RG7112 (RO5045337) [38]. The majority of patients who accepted treatment with RG7112 had a stable disease. While nutlins can strongly activate wtp53 in tumors overexpressing MDM2, they are unable to activate the p53 pathway in cancers overexpressing MDMX due to subtle differences in the N-terminal p53-binding pocket of MDMX [39]. ALRN-6924 was the only dual MDM2 and MDMX inhibitor to reach clinical trials after preclinical investigations revealed a considerable antitumor effect [40, 41]. Since MDM2 and MDMX have distinct anti-p53 activities, dual antagonists targeting both p53-MDM2 and p53-MDMX may have a greater effect than inhibiting either pathway alone.
In addition to reactivating mutp53, selective targeting of mutp53 proteins may also exhibit an antitumor effect [15]. This compound development strategy is based on the following observations: (1) depletion of mutp53 by siRNA or shRNA can suppress the mutp53-mediated malignant progression and (2) mutp53 is inherently unstable [51,52,53]. Therefore, the cornerstone of this strategy is to restrict the expression of mutp53 and promote the degradation of mutp53 (Table 3).
Although mutp53 preferentially exhibits glycolysis-promoting functions, several cancer cells with mutp53 display enhanced mitochondrial functions. Eriksson et al. found that H1299 cells induced with p53 R175H and R273H showed enhanced mitochondrial respiration capacity [91]. This finding suggested the possibility of targeting OXPHOS for cancer therapy with mutp53. Additionally, inhibiting OXPHOS could be regarded as a combination regimen with glycolysis inhibitors. This approach showed feasibility, as cotreatment with 2-deoxyglucose (glycolytic inhibitor) and metformin (OXPHOS inhibitor), had a significant effect on prostate cancer cells compared to monotherapy [92]. However, in our opinion, targeting OXPHOS might be a riskier strategy as OXPHOS is the major energy resource of normal cells. Moreover, Warburg metabolism is a common metabolic alteration in cancer cells instead of an advantage of cancers with p53 mutations. Herein, screening synthetic lethal partners with mutp53 in the field of energy metabolism should integrate the specific genetic alteration of mutp53.
Due to the high frequency of p53 mutations, it is an appealing target for therapeutic strategies. The most convenient strategy is to directly target p53. In cancers where p53 is intact, inhibiting its negative regulator MDM2/X can activate the native tumor-suppressive function of p53. However, a significant limitation of this approach is the adverse event caused by widespread wtp53 activation in normal tissues [61]. It is preferable to develop a drug delivery system capable of transporting drugs specifically into tumors. For instance, nanomedicine-based therapy can significantly enhance drug efficacy while minimizing adverse effects [142]. Moreover, MDM2 inhibitor monotherapy is insufficient to completely suppress tumor progression. Thus, exploring a combination regimen of MDM2 inhibitors with other treatments may be a prospect for anticancer strategies [143]. For the strategies to reactive or deplete mutations, challenges arise from the determination of mutp53 protein structure [144]. Multiple p53 mutations necessitate the use of multiple agents directed against mutp53, let alone the specific and effective functions of the mutp53 reactivator/inhibitor.
As an important but highly mutated tumor-suppressive gene, p53 is an attractive therapeutic target for cancer therapy. Reactivating the functions of tumor-suppressive factors is more challenging than directly inhibiting oncogenic factors. Direct targeting of the mutp53 protein is highly dependent on the unique structures of the protein, which makes drug development more complex and limits the applications of drugs. The indirect strategy, which is based on the concept of synthetic lethality, targets the unique vulnerabilities or alterations caused by mutp53 functional defects or acquired oncogenic functions. The synthetic lethality-based approach targeting mutp53, such as utilizing PARP inhibitors to treat cancers harboring BRCA1/2 mutations, can kill tumors with mutp53 while having no or little negative effects on normal cells or tissues. The development of synthetic lethality strategies with mutp53 can bring extensive benefits to patients. Due to the shortcomings in the G1 arrest of TP53-mutated malignancies, current studies focus on the suppression of G2 arrest. However, more studies should be conducted to improve the efficacy of monotherapy, limit the side effects of combination therapies, and expand the repertoire of mutp53 synthetic lethal partners. Based on the research of ncRNAs in cancer, it is reasonable to investigate ncRNAs for synthetic lethality. Although the use of ncRNAs as therapeutic targets for cancer is still in its early stages, it has the potential to expand and fulfil the synthetic lethal network of mutp53. In general, TP53 is an attractive therapeutic target for cancer, and the development of synthetic lethality with mutp53 will considerably expand clinical options for cancer patients. Furthermore, as more treatments targeting p53 are being developed, it will be feasible to design personalized treatment plans according to the p53 mutation of patients.
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