Current developments of targeting the p53 signaling pathway for cancer treatment

Abstract

p53 is one of the most well-studied tumor suppressors. It is mutated or deleted in half of all cancers. In the other half carrying wild type p53, the p53 signaling pathway is disrupted by abnormalities of other components in the pathway. Due to its paramount role in tumor suppression, p53 has attracted great interest in drug development as any clinically successful therapeutic agent to target the p53 pathway will save millions of lives. However, designing therapeutics targeting the pathway has been extremely challenging, despite more than forty years of research. This review will summarize past and current efforts of developing p53-based gene therapy and targeted therapies for cancer treatment. In addition, the current efforts of exploiting the immunogenicity of p53 protein for cancer immunotherapy will be reviewed. Challenges and future directions for targeting the p53 pathway will be discussed.

Keywords: Cancer; Cancer therapy; Gain of function; Immunotherapy; Tumor suppressor; p53.

Figure 1.. A schematic showing the p53 signaling pathway under unstressed and stressed conditions.

Under the unstressed condition, p53 is ubiquitylated by MDM2 and other E3 ligases and subsequently degraded by the proteasome machinery. Under stressed conditions, p53 is activated and post-translationally modified. Some of these modifications prevent p53 from E3-mediated degradation and increase the steady-state levels of p53. Activated p53 binds to chromatin and regulates transcription of its targets, which mediates various cellular functions of p53. These cellular functions are thought to contribute to the tumor suppressive function of p53. Red lollipops: post-translational modifications (PTMs); Blue beads on a string: nucleosomes.

Figure 2.. Strategies of targeting cancer cells carrying WT p53, mutant p53, or p53 deletion.

Strategies for each type of cancer cells are highlighted in red. Adenovirus-based gene therapy, chemo and radiotherapy, MDM32 and MDMX inhibitors can be used to target cancer cells carrying wild type p53. Gene therapy, compounds restoring WT conformation, HSP inhibitors, immunotherapy, and inhibition of synthetic lethal genes can be used for targeting cancer cells carrying mutant p53. For targeting cancer cells with p53 deletions, gene therapy and inhibition of synthetic lethal genes can be used.

Figure 3.. A framework of exploiting the immunogenicity of p53 mutants for the adoptive cell transfer.

Tumor cells carrying mutant p53 or apoptotic bodies can be engulfed by antigen presenting cells (APCs). The MHC II of APCs presents mutant p53-derived neoantigens to CD4+ T cells, which help B cells produce antibodies against the neoantigens. Most tumor cells express MHC I, which self-presents mutant p53-derived neoantigens. CD8+ T cells are activated through the interaction between MHC I and T cell receptors (TCRs). Activated CD8+ T cells (cytotoxic T cells) can attack tumor cells. The tumor infiltrated lymphocytes (TILs), containing mostly CD8+ T cells and natural killer (NK) cells, can be isolated from tumors, propagated to a large number ex vivo, and given back to the patients to attack the tumors. TCRs specific to mutant p53-neoantigens can be cloned and packaged into viral particles to generate either TCR-T cells or CAR-T cells, which are infused back into the same patients.