Targeting mutant p53 for cancer therapy: direct and indirect strategies

Abstract

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.

Keywords: Cancer therapy; MDM2 inhibitor; Noncoding RNA; Synthetic lethality; p53; p53 restoration.

Fig. 1

The functions of p53 in the normal cells. p53 is an important tumor suppressor in normal cells to maintain homeostasis. Throughout their lifespan, cells are faced with continuing stresses including endogenous and exogenous stresses. To overcome these stresses, p53 is activated to mediate a series of cellular responses via its transcription-dependent functions or direct protein-to-protein interactions. p53-mediated responses also rely on the type and degree of insults, as well as the cell types and the context in which the insult occurs

Fig. 2

Multiple anticancer therapeutic strategies targeting p53. The p53 protein, encoded by the TP53 gene, consists of five functional regions: TA, PR, DBD, OD, and CTD. (Left) After being imported into the nucleus and tetramerized, wtp53 proteins acquire the ability to bind with their target genes (e.g., p21, Bax, PIGs, PAI) to induce tumor-suppressive responses (cell cycle arrest, apoptosis, and senescence) to suppress tumor initiation or progression. The ubiquitin E3 ligase MDM2 directly binds to p53 proteins and promotes proteasomal degradation. For cancers containing wtp53, MDM2 inhibitors (e.g., AMG232 and RG7388) prevent p53 from proteasomal degradation and promote its tumor-suppressive functions via disrupting the p53-MDM2 protein–protein interaction. (Right) Most mutations of mutp53 proteins occur in the DBD regions, including several hotspot mutation sites (175, 220, 245, 248, 249, 273, 282). Mutp53 proteins lose the ability to bind with tumor-suppressive genes and even acquire functions to transcriptionally activate oncogenic genes (e.g., NF-κB2, TGFβ-R2, BRCA1) to induce tumor-promoting responses such as inflammation and metabolic reprogramming. Mutp53 reactivators target specific p53 mutations (e.g., APR-246 targets p53 R175H and R273H, and COTI-2 targets p53 R175H) to restore wtp53 functions. Additionally, mutp53 inhibitors directly bind to mutp53 (e.g., HDAC inhibitor for p53 R175H, R280K and V247F/P223L, and disulfiram for p53 R273H) to promote degradation. TA: transactivation domain; PR: proline-rich domain; DBD: DNA-binding domain; OD: oligomerization; CTD: carboxyl-terminal domain; Ub: ubiquitin

Fig. 3

Synthetic lethality with mutp53 LOF and GOF. A Wtp53 maintains the survival-promoting pathways when cells undergo stress. Mutp53 loses these functions but activates compensatory pathways to protect cancer cells from lethal stresses. Thus, these compensatory pathways become vulnerable in cancers as these pathways are less dependent on normal cells. Taking the role of p53 in cell cycle arrest as an example, in response to DNA damage, wtp53 can activate p21 to induce G1 arrest to repair DNA damage (left). Under conditions of p53 mutation, cancer cells rely more on S and G2 arrest for DNA repair. Inhibition of regulators of S and G2 arrest results in the accumulation of unpaired DNA and mitotic catastrophe (right). B For mutp53 GOFs, the target genes upregulated by mutp53, which are usually silenced when p53 is not mutated, might be the crucial factors promoting tumor progression. Targeting these genes can selectively suppress the cancer progression of cancers with mutp53. Regarding energy metabolism, wtp53 inhibits glycolysis and promotes OXPHOS (left), and mutp53 acquires the opposite functions to promote glycolysis and inhibit OXPHOS (right). Herein, targeting the enhanced glycolysis induced by mutp53 can be developed for synthetic lethal approaches