Scientists have struggled for decades to understand why radiation therapy kills cells from the same tumor in different ways. This is important because some forms of cell death go unnoticed by the immune system, while others trigger an immune response that kills other cancer cells.
New research, published in the journal “Nature Cell Biology”, reveals for the first time how DNA repair, which normally protects healthy cells, determines how cancer cells die after radiation therapy.
The solution to this mystery, discovered by a team of scientists from the Pediatric Medical Research Institute (CMRI) led by Professor Tony Cesare and whose first author is Dr Radoslaw Szmyd, opens new opportunities to improve treatment and increase survival rates. healing.
Freeing the patient’s immune system to kill cancer cells and eliminate tumors is a major goal of cancer treatment.
“The surprising result of our research is that DNA repair determines how cancer cells die after radiotherapy,” says Professor Cesare.
“The DNA inside our cells is constantly damaged, and DNA repair occurs all the time to repair that damage and keep our cells healthy. Now, however, he continues, it seems that These repair processes can recognize when overwhelming damage has occurred (for example, due to radiation therapy) and give instructions to a cancer cell how to die.
“When DNA damaged by radiotherapy was repaired using a method called homologous recombinationthe cancer cells died during the process of reproduction, a process called cell division or mitosis. Crucially, death during cell division goes unnoticed by the immune system, so it will not trigger an immune response. This is not what we want,” he explains.
“However, cells that dealt with radiation-damaged DNA through other DNA repair methods survived the cell division process, but they did so by releasing DNA repair byproducts into the cell. For the cell, these Repair byproducts look like a viral or bacterial infection. This makes the cancer cell dies in a way that alerts the immune system. Which is what we want,” he adds.
The team showed that Blocking homologous recombination changed how cancer cells diedthat is, they died in a way that caused a strong immune response.
The team also found that cancer cells that have mutations inBRCA2 (a very important gene for breast cancer and is necessary for homologous recombination) they do not die in mitosis after radiotherapy.
In addition to solving an important scientific puzzle, these discoveries will make it possible to use drugs that block homologous recombination to force cancer cells treated with radiation therapy to die in a way that alerts the immune system to the existence of cancer (which the system immune system had not previously been detected), indicating that it needs to be destroyed.
Professor Cesare attributes these advances to live cell microscope technology that allowed his team to follow irradiated cells for a week after radiotherapy: “Live images showed us the full complexity of the results after radiotherapy, which which allowed us to find out exactly why this happened.”
Project co-leader Associate Professor Harriet Gee, a radiation oncologist at the Western Sydney Local Health District Radiation Oncology Network, said these findings answer a clinical question that has baffled the field for 30 years: “We have discovered that the way tumor cells die after radiotherapy depends on the activation of specific DNA repair pathways, particularly when radiation is delivered at very high and focused doses. “This opens up new opportunities to improve the effectiveness of radiation by combining it with other therapies, particularly immunotherapy, to increase cancer cures.”
Professor Cesare said that Dr Szmyd worked for six years on this “incredibly difficult problem to solve” and that “everyone knows that there are patients fighting cancer. “To discover something like this, which has the potential to make a big difference to people’s lives, is very rewarding.”
