Research News

Physician scientists from Cleveland Clinic have demonstrated that endometrial cancer cells with p53 gene mutations are more resistant to radiation. Combining radiation with MDM2 inhibitors strengthens non-mutated P53 proteins, boosting the effects of radiation 

The research was published in npj Precision Oncology, and was led by Roberto Vargas, MD, in collaboration with Jacob Scott, MD, DPhil. Their findings offer a promising path toward more personalized treatment for endometrial cancer. Endometrial cancer is the only cancer where survival rates have not improved in the past 30 years, based on cancer statistics from 2025.  

Dr. Vargas’s interest in studying endometrial cancer originated in the clinic, where he treats women and individuals with gynecologic cancers.  

“Endometrial cancer is 5-6 times more common than ovarian cancer, so it's the highest volume of cancers that I treat,” he explains. “It's becoming more common, and everyone is losing more patients to it. It’s a growing problem where we need to invest time and energy trying to improve our care.”  

p53 gene mutations impact how well endometrial cancer treatment works  

Dr. Vargas had seen in the clinic that patients with some of the deadliest forms of endometrial cancer had mutations in the gene (TP53) responsible for the p53 protein. Dr. Vargas led his team in a series of rigorous laboratory experiments to assess how, if at all, p53 status directly impacts how endometrial cancer cells respond to radiotherapy.  Radiation remains a large piece of the standard of care in early and late-stage endometrial cancer.  

First, they performed in vitro (petri dish) experiments using different endometrial cancer cells. Some had normal p53 and others had mutated p53. The cancer cells with p53-mutant status tolerated higher radiation doses than the cells with normal (wild-type) p53.  

The team then used CRISPR to alter the p53 gene in the wild-type p53 cancer cells, and to repair the p53 gene in p53-mutated cancer cells. The “fixed” cells that previously resisted radiotherapy now responded well to treatment, while the “broken” cells that responded well now resisted radiotherapy.  

Dr. Vargas’s research is among the first to show that p53 mutations don't just signal a poor prognosis in endometrial cancer; they play an active role in the way patients respond to radiation.  

“Prognostic markers only let me estimate a patient’s overall outcome regardless of what treatment I prescribe. They don’t give me actionable next steps,” he explains. “Knowing that mutated p53 may actually be predictive, can tell me how the presence of the mutation in the gene may affect my patients’ individual response to therapy. This helps inform their treatment plan.”  

After showing how p53 status directly impacted how well a tumor responded to radiation therapy, Dr. Vargas wanted to know how they could use this to improve radiation effect.  

Using what we know about the role of p53 gene mutations to inform treatments for endometrial cancer  

As the normal function of p53 is well studied, the team was able to show how gene mutations helped tumor cells survive radiation. When our DNA is too damaged to repair, p53 is responsible for telling our cells to die by triggering a process called apoptosis. This keeps the damaged DNA from spreading being copied forward and making us sick. Radiation therapy takes advantage of this process. The radiation damages our DNA and wild type p53 tells our cells to start apoptosis. 

Endometrial cancer cells with mutated p53 do not produce the normal signals to trigger apoptosis. They survive radiotherapy, all the while accumulating even more harmful DNA alterations.  

“The thing about endometrial cancer is that some p53-mutated tumors will still have a copy of the healthy / wild-type gene,” he says. “We had the idea that if we could boost the healthy copies, we might be able to make up for mutated p53 copies within the cell.”  

The team used experimental compounds called MDM2 inhibitors to help healthy p53 proteins stay active in the cancer cells longer by preventing their breakdown. In preclinical testing, cancer cells died faster and at lower doses than either radiotherapy or MDM2 inhibitors alone, and even more than the team had anticipated from simply combining them.  

“More research is necessary to confirm, but this seems to be an optimal combination therapy we can use to treat endometrial cancers without p53 mutations, which are 80% of our cancers,” Dr. Vargas says. “It may even be a way for us to reduce radiation doses across the board to reduce side effects without compromising the treatment.”