p53 is a Key Tumor Suppressor and is Central to Cancer Treatment
The p53 protein plays a central role in the human body’s defenses against cancer. When DNA is damaged inside a cell, p53 is activated and can initiate a cascade of events called apoptosis that destroys the cell before it can become cancerous. By eliminating high-risk cells p53 suppresses the formation of tumors. However, when p53 activity is compromised then this protective function is shut off and cancerous cells can replicate to produce a tumor. In addition to its key role is preventing cancer, p53 is also central to the effective treatment of cancer with chemotherapy. Many anticancer drugs work by inducing DNA damage, thereby activating p53 and triggering elimination of cancer cells via apoptosis.
Mutated p53 is a Prime Target for Novel Cancer Therapies
Like the rest of the human genome, the DNA that encodes the gene for p53 can have mutations that are inherited or environmentally-induced. Some of these mutations have little or no impact on p53 function but others may inhibit this important protein from properly carrying out its normal activities or may even endow p53 with new and undesirable functions. Changes in p53 activity not only can prevent the elimination of potentially cancerous cells but also may facilitate tumor growth.
The p53 gene is the most frequently mutated gene in human cancers, with mutations found in more than 50% of all tumors. Tumors with mutated p53 often show increased resistance to standard chemotherapy regimens and have a poor clinical prognosis. Although many p53 mutants have been identified, a small number of these are found to be common across tumor types.
The high prevalence of p53 mutants in human tumors establishes this protein as a prime target for anticancer therapies. However, the number of known mutations and the potential for multiple mutations to be present in a single p53 protein create a diverse spectrum of dysfunctional p53 proteins, each with a unique molecular shape and biological properties. Furthermore, specific p53 mutations can vary across tumor types and between patients, and cells within a tumor may express multiple forms of dysfunctional p53. Therapeutic agents that target a single form of mutant p53 would therefore be of limited benefit. In contrast, development of drugs that can effectively target a wide range of p53 mutants, and restore normal p53 activity, would represent a significant advance for the treatment of cancer.