Researchers at Baylor College of Medicine have identified that certain mutations in the p53 gene, which is known for its role as a tumor suppressor, could be leveraged to improve cancer treatment strategies. The p53 gene, often referred to as the "guardian of the genome," is crucial for maintaining genomic stability and preventing cancer-causing mutations. However, when mutated, p53 can lose its protective function and contribute to aggressive cancer growth. About half of all human cancers carry a mutation in this gene.
The study, published in Communications Biology, focused on two common p53 mutants: R273H and R175H. Dr. Weei-Chin Lin, professor of molecular and cellular biology at Baylor College of Medicine and medicine – hematology and oncology at Baylor’s Dan L Duncan Comprehensive Cancer Center, explained their approach: “We studied two common p53 mutants, R273H and R175H, in their ability to affect the growth of cancer cell lines in the lab,” said Lin. “We took a closer look at how each of these mutants affected different steps of the complex mechanism of DNA replication, a first stage in cell proliferation.”
Their research showed that the R273H mutation leads to excessive DNA replication and rapid cancer cell proliferation. Notably, this overactive replication also triggered an immune response through activation of the cGAS-STING pathway—a part of the body’s innate immune system. Lin stated: “However, we were surprised to see that at the same time, excessive DNA proliferation triggered a strong immune response toward the cancer cells. This response was driven by activation of the cGAS-STING pathway, a key part of the body’s innate immune response. In contrast, the other mutant, R175H, behaved differently. Although this mutation promoted cancer growth, it did not trigger an immune response toward cancer cells. This highlights the importance of understanding the specific type of p53 mutation in each patient’s tumor, as it may influence both disease behavior and therapeutic strategies.”
Further experiments using mouse models with breast cancer revealed that tumors with the R273H mutation responded more favorably to immune checkpoint inhibitors—a therapy designed to help the immune system target cancer cells—than those without this specific mutation. Tumors treated with these inhibitors had increased levels of CD8+ T cells actively attacking cancer cells.
These findings suggest that identifying specific p53 mutations like R273H could help predict which patients are more likely to benefit from immunotherapy treatments such as immune checkpoint inhibitors. According to Lin: “Although more studies are needed before these findings could be implemented in the clinic, they offer the possibility that doctors might be able to predict which patients will respond better to immunotherapy by identifying tumors with mutant p53 variants like R273H.”
Lin also noted potential future directions: “Our study also suggests that combining immunotherapy with drugs that target DNA replication could further enhance the immune response in these patients,” he said. “The findings open up new avenues for future personalized cancer treatment.”
Kang Liu was first author on this study along with Lidija A. Wilhelms Garan and Fang-Tsyr Lin—all affiliated with Baylor College of Medicine.
The research received support from multiple sources including NIH grants (R01CA203824 and R01CA269971), Department of Defense grants (W81XWH-18-1-0329, W81XWH-19-1-0369, W81XWH-22-1-0226, W81XWH-22-1-0534, HT9425-24-1-0045), a Rivkin Center for Ovarian Cancer Pilot Award and T32GM136560.
