Some p53 mutations could help fight cancer

The gene p53 acts as a tumor suppressor and often is called the ‘guardian of the genome.’ This gene is central to maintaining genomic stability, which prevents mutations from accumulating and leading to cancer. But when p53 mutates, it can flip from protector to promoter of cancer. These mutations often disable p53’s protective functions and give cancer cells the ability to grow aggressively. Gene p53 is mutated in about 50% of human cancers, yet, despite its central role in cancer biology, it has remained unclear whether specific p53 mutations could be used to guide cancer treatment strategies.

Bringing new insights into this topic, researchers at Baylor College of Medicine have discovered that certain p53 mutants hijack the DNA replication machinery causing it to fire excessively, destabilizing the genome. Their study, published in Communications Biology, reveals that these mutant forms of p53 could be exploited to help fight cancer.

“We studied two common p53 mutants, R273H and R175H, in their ability to affect the growth of cancer cell lines in the lab,” said corresponding author Dr. Weei-Chin Lin, professor of molecular and cellular biology at Baylor and of medicine – hematology and oncology at Baylor’s Dan L Duncan Comprehensive Cancer Center. “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.”

The researchers found that p53 mutation R273H causes excessive DNA replication, which leads to aggressive cell proliferation promoting cancer growth. “However, we were surprised to see that at the same time, excessive DNA proliferation triggered a strong immune response toward the cancer cells,” Lin said. “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.”

The team tested in mouse models of breast cancer whether tumors with the R273H mutation responded better to a type of therapy that helps the immune system attack cancer, called immune checkpoint inhibitors. Tumors carrying the p53 R273H mutation that were treated with immune checkpoint inhibitors had more CD8+ T cells – a type of cancer fighting immune cells – and showed signs that the immune system was actively killing cancer cells.

This discovery could have major implications for cancer therapy. Immune checkpoint inhibitors have revolutionized treatment for many cancers, but they don’t work for everyone. “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.”

“Our study also suggests that combining immunotherapy with drugs that target DNA replication could further enhance the immune response in these patients,” Lin said. “The findings open up new avenues for future personalized cancer treatment.”

First author Kang Liu, Lidija A. Wilhelms Garan and Fang-Tsyr Lin, all at Baylor College of Medicine, contributed to this work.

This work was supported by funding from 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 by T32GM136560.

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