A new study is the first to resolve the debate over how a mutated protein found in half of human cancers drives tumor growth. The discovery not only helps rethink the way cancer is treated, but may also lead to new and improved treatments. Normally, the TP53 gene provides instructions for making the p53 protein, which plays a key role in repairing or, if repair cannot be done, destroying damaged cell DNA. It is a tumor suppressor that regulates cell division and prevents cells from proliferating too quickly or out of control.
p53 mutations are present in half of human cancers and can be triggered by environmental factors (such as exposure to ultraviolet radiation) or genetic factors. However, opinions differ as to whether mutations result in loss or gain of p53 function. Loss of function means the protein cannot regulate the cell's response, preventing tumor development and growth, while gain of function results in a super-powerful protein that helps cancer cells survive and proliferate.
In a new study, researchers from Australia's Walter Eliza Hall Institute (WEHI), in collaboration with the University of Trento in Italy, resolve this debate, discovering for the first time which features of the mutant p53 protein are critical in driving cancer growth.
Gemma Kelly, co-corresponding author of the study, said: "Looking at all cancers in humans, p53 mutations are present in about 50% of cancers. Certain cancers, such as pancreatic, lung and breast cancer, often have defects in these proteins. Our findings change our understanding of these mutations and help rethink how to target them when developing new cancer treatments."
The researchers used CRISPR/Cas9 technology to genetically inactivate 12 different mutant TP53 genes, which were reported to produce gain-of-function activity in human cancer cell lines. They found that removing mutant p53 had no effect on the survival or proliferation of the cancer cell lines tested in vitro. It also did not affect mitochondrial content or activity, or intracellular levels of reactive oxygen species (ROS); increased cellular metabolism and elevated intracellular ROS levels are hallmarks of cancer.
It has been reported that the gain-of-function effects of mutated p53 help cancer cells adapt to stresses such as lack of nutrition, or become resistant to anticancer drugs. When the researchers starved TP53-deficient cells of nutrients and exposed them to various chemotherapy drugs, they observed that continued expression of mutant p53 was not necessary for the cancer cells to adapt.
Immunodeficient mice are considered the gold standard model for studying human tumor growth. After xenografting human and mouse cancer cell lines and patient colon cancer-derived organ tissue into immunodeficient mice, they found that removing mutated p53 did not affect tumor growth or metastasis. Additionally, in preclinical models, restoring the normal function lost after mutations in the p53 protein reduced cancer growth.
"Our study provides the first evidence that it is actually loss of function that affects cancer growth," Kelly said. "We found no evidence that gain of function contributes to cancer growth."
To expand the scope of their study, the researchers mined data from the Cancer Dependence Map (DepMap), an ongoing project to identify cancer-related genes, and examined the effects of deleting mutant TP53 on the growth and survival of 391 different types of human cancer cell lines. The results "unequivocally" showed that deleting mutant TP53 did not affect the growth of any cancer cell lines.
Wang Zilu, the first author of the study, said: "With these tools, I can evaluate 157 different p53 mutations. The mutations I studied basically account for at least 90% of human cancers with p53 defects, which will provide crucial insights for the development of new anti-cancer strategies."
The researchers say their discovery could prevent hundreds of millions of dollars from being wasted on developing ineffective drugs.
Andreas Strasser, another corresponding author of the study, said: "Research is currently underway to find the first treatments that target gain-of-function traits. Our results indicate that this therapeutic approach has no further value and the focus needs to shift to restoring the lost function of the mutant protein and normal tumor suppressive ability."
The study was published in the journal Cancer Discovery.