Targeting the Oncogenic p53 Mutants in Colorectal Cancer and Other Solid Tumors

Abstract

Colorectal cancer (CRC) is a kind of solid tumor and the third most common cancer type in the world. It is a heterogeneous disease characterized by genetic and epigenetic aberrations. The TP53 mutation is the key step driving the transition from adenoma to adenocarcinoma. The functional roles of TP53 mutation in tumor development have been comprehensively investigated. In CRC, TP53 mutation was associated with poor prognosis and chemoresistance. A gain of function (GOF) of p53 mutants promotes cell proliferation, migration and invasion through multiple mechanisms. Restoring wild type p53 function, depleting p53 mutants, or intervention by targeting the oncogenic downstreams provides potential therapeutic strategies. In this review, we comprehensively summarize the GOF of p53 mutants in CRC progression as well as in some other solid tumors, and discuss the current strategies targeting p53 mutants in malignancies.

Keywords: TP53; colorectal cancer; p53 mutants; solid tumor.

Figure 1

The consequences of somatic TP53 mutations in tumorigenesis. The outcomes of p53 mutants are loss of wild type function and gain of new function. The LOH (loss of heterozygosity) and DNE (dominant-negative effect) are the two major main mechanisms to abrogate the tumor suppressor function of wild type p53. In some cancer cases with TP53 mutations, the GOF (gain-of-function) of p53 mutants are empowered with kinds of oncogenic potentials, which promote cancer initiation and progression.

Figure 2

The multiple mechanisms of p53 mutants with GOF in CRC and other solid tumors. Upper, p53 mutants bind to TF (transcription factor) and activates target gene expression, such as c-Myc and Bcl-XL. Middle, p53 mutants bind to TFs (p63 and p73) and subvert their binding affinities to targeted promoters, which suppresses target gene expression. Lower, p53 mutants bind to and activate chromatin modifying enzymes to remodel the chromatin and promote target gene transactivation.

Figure 3

Strategies targeting p53 mutants with GOF. The strategies have been extensively undertaken to develop small molecular compounds that specifically target p53 mutants. The detailed mechanisms include restoring p53 wild type function, depleting p53 mutants, inducing synthetic lethality of p53 mutants and inhibiting the oncogenic downstream targets of p53 mutants. The cysteine-binding compounds, Zn2+-chelating compounds, peptides and other types’ compounds are employed to reactivate p53 wild type function, which are listed in the frame on the left. The compounds inducing p53 mutant depletion are listed in the right frame. The upper frame demonstrates the compounds which could induce synthetic lethality, including UCN01, BI-2536 and PD0166285. Statins and Integrin inhibitor have been reported to successfully inhibit p53 mutants’ downstream targets.