p53 mutations in colorectal cancer- molecular pathogenesis and pharmacological reactivation

Abstract

Colorectal cancer (CRC) is one of the most common malignancies with high prevalence and low 5-year survival. CRC is a heterogeneous disease with a complex, genetic and biochemical background. It is now generally accepted that a few important intracellular signaling pathways, including Wnt/β-catenin signaling, Ras signaling, and p53 signaling are frequently dysregulated in CRC. Patients with mutant p53 gene are often resistant to current therapies, conferring poor prognosis. Tumor suppressor p53 protein is a transcription factor inducing cell cycle arrest, senescence, and apoptosis under cellular stress. Emerging evidence from laboratories and clinical trials shows that some small molecule inhibitors exert anti-cancer effect via reactivation and restoration of p53 function. In this review, we summarize the p53 function and characterize its mutations in CRC. The involvement of p53 mutations in pathogenesis of CRC and their clinical impacts will be highlighted. Moreover, we also describe the current achievements of using p53 modulators to reactivate this pathway in CRC, which may have great potential as novel anti-cancer therapy.

Keywords: Colorectal cancer; p53; Tumor suppressor; Small molecule inhibitor; Gene therapy; PRIMA-1^MET

Core tip: Dysregulation of p53 tumor suppressor gene is one of the most frequent events contributing to the transformation of colorectal cancer (CRC), as well as the aggressive and metastatic features of CRC. Mutant p53 reactivator, PRIMA-1^MET has been tested in Phase I/II clinical trials and shows encouraging benefits. In this review, we systemically and comprehensively summarize the current understanding of p53 mutations in the pathogenesis of CRC and current progress in reactivation of p53 as a novel therapeutic strategy. We hope this review will promote more investigations of reactivation of p53 as a viable treatment option of patients with CRC.