Molecular Targeting of the Most Functionally Complex Gene in Precision Oncology: p53

Simple Summary Precision medicine is a powerful treatment modality for controlling tumor growth. However, given the substantial variability between cancer patients, identifying suitable targets is no easy task. Tumor protein p53 represents one of the most promising anti-cancer drug targets due to its high mutation rate and critical role in tumorigenesis. Despite this, current treatment strategies targeting p53 signaling have only seen modest clinical success presumably due to the complex signaling network surrounding p53 enabling cancer cells to have the ability to adapt to each treatment strategy. This review will focus on the multiple approaches to target p53 and will touch on some of the limitations that may be hindering their clinical success. While chemotherapy is a key treatment strategy for many solid tumors, it is rarely curative, and most tumor cells eventually become resistant. Because of this, there is an unmet need to develop systemic treatments that capitalize on the unique mutational landscape of each patient's tumor. The most frequently mutated protein in cancer, p53, has a role in nearly all cancer subtypes and tumorigenesis stages and therefore is one of the most promising molecular targets for cancer treatment. Unfortunately, drugs targeting p53 have seen little clinical success despite promising preclinical data. Most of these drug compounds target specific aspects of p53 inactivation, such as through inhibiting negative regulation by the mouse double minute (MDM) family of proteins. These treatment strategies fail to address cancer cells' adaptation mechanisms and ignore the impact that p53 loss has on the entire p53 network. However, recent gene therapy successes show that targeting the p53 network and cellular dysfunction caused by p53 inactivation is now possible and may soon translate into successful clinical responses. In this review, we discuss p53 signaling complexities in cancer that have hindered the development and use of p53-targeted drugs. We also describe several current therapeutics reporting promising preclinical and clinical results.