The effectiveness of radiotherapy in killing cancer cells depends on the DNA repair pathway the cell uses to fix radiation-induced damage.
Researchers from the Children's Medical Institute (CMRI) at the University of Sydney, Australia, have discovered that a cell's response to radiotherapy depends on the DNA repair mechanism it employs. Radiotherapy, a common cancer treatment, works by damaging the DNA of cancer cells. However, the reasons behind varied responses to the treatment have remained unclear. Now, the researchers have found that in some instances the radiotherapy-induced damage triggers an immune response to kill the cancer cells, whereas in other instances it can go unnoticed by the immune system.
'The surprising result of our research is that DNA repair, which normally protects healthy cells, determines how cancer cells die following radiotherapy,' said Professor Tony Cesare, joint senior author and head of CMRI's genome integrity unit. 'It turns out that these repair processes can recognise when the damage is overwhelming, such as with radiation, and can instruct a cancer cell how to die.'
Publishing their findings in Nature Cell Biology the researchers used advanced live-cell imaging to observe cells up to a week following radiation therapy, allowing them to capture the entire process of cell death. They found that where DNA damage is excessive or irreparable, such as that caused by radiation therapy, homologous recombination, a type of DNA double-strand break repair pathway, can promote cell death during mitosis. This remains hidden from the immune system.
In contrast, if an alternative repair pathway is used, such as non-homologous end joining or single-strand annealing, cell death is delayed during mitosis and interferons are produced. This more effectively flags the cancer to the immune system, similarly to a bacterial infection, prompting rapid cancer cell destruction.
The researchers also studied cancer cells with specific BRCA2 mutations, a gene that is vital for homologous recombination. Certain mutations in the BRCA2 gene are also known to increase the risk of developing breast, ovarian and prostate cancers. They found that after radiotherapy, the cancer cells with the BRCA2 mutations, and hence a defective DNA repair mechanism, did not die during mitosis and were more likely to survive and spread.
Furthermore, combining radiotherapy with a homologous recombination inhibitor, yielded greater therapeutic benefit by activating an alternative repair pathway that triggers a response from the immune system.
These new insights suggest that using DNA repair pathway inhibitors could improve the treatment of specific cancers as part of a personalised approach.
'We found that the manner in which tumour cells die after radiotherapy depends on the engagement of specific DNA repair pathways, particularly when radiation is given at very high, focused doses,' commented Dr Harriet Gee, a radiation oncologist from the Western Sydney Local Health District Radiation Oncology Network, Australia, and joint senior author. 'This opens up new opportunities to enhance radiation efficacy through combination with other therapies, particularly immunotherapy, to increase cancer cures.'
Sources and References
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Breakthrough in understanding how tumour cells die after radiotherapy
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Homologous recombination promotes non-immunogenic mitotic cell death upon DNA damage
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Different DNA repair mechanisms drive cancer cell death after radiotherapy
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DNA repair pathways influence cancer cell death after radiotherapy, study finds
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