Abnormal protein activity may contribute to DNA damage in cancer cells

Overproduction of a DNA repair protein called EXO1 can trigger DNA damage and increase chemotherapy sensitivity in human cancer cells, a new study has reported.

BRCA1 and BRCA2 are tumour suppressor genes that repair damaged DNA, and mutations in these sequences are associated with increased risk of breast and ovarian cancers. However, most tumours retain normal BRCA function, suggesting that other mechanisms contribute to DNA damage in cancer. Researchers from Pennsylvania reported that EXO1 is present at unusually high levels in various cancer types, and demonstrated that EXO1 overexpression can induce DNA damage and increase sensitivity to chemotherapy drugs, despite normal BRCA function.

'EXO1 could potentially serve as a biomarker to help predict which patients are more likely to respond to certain chemotherapy treatments,' said Professor George-Lucian Moldovan from the Penn State Cancer Institute, in Philadelphia, corresponding author of the study published in Nature Communications. 'The same drugs that are reserved for treating BRCA-mutant tumours could potentially be used to treat EXO1 overexpressing tumours, which don't have BRCA mutations. It would expand the applicability of those drugs.'

To investigate whether alterations in EXO1 are associated with cancer, the researchers first analysed the Pan-Cancer Atlas, a publicly available resource containing genetic and molecular data from more than 11,000 tumours across 33 cancer types. EXO1 was overexpressed in several types of tumour samples, driven either by increased mRNA levels or the presence of extra gene copies. These changes were most common in breast cancer – affecting 21 percent of cases – but were also observed in melanoma, testicular and cervical cancers, alongside cancers of the liver, gall bladder and bile duct.

Next, the authors overexpressed EXO1 in two human cancer cell lines derived from cervical and bone tumours, both of which retain normal BRCA-mediated DNA repair. When these cells were exposed to anti-cancer treatments, those with elevated EXO1 levels accumulated more DNA damage.

The cells were subsequently tested with treatments used in BRCA-related cancers. EXO1 overproduction increased sensitivity of the cells to olaparib, a medication that targets DNA repair, and also to cisplatin, a widely used chemotherapy drug.

'EXO1 overexpression leads to the generation and accumulation of toxic lesions in DNA, such as double-strand breaks, which we ultimately think is what makes the tumour more sensitive to chemotherapy and increases cell death,' explained Alexandra Nusawardhana, lead author and PhD student at Pennsylvania State University.

In the future, the authors plan to continue this line of research, with the long-term aim of advancing towards clinical trials in cancer patients presenting with tumours that overproduce EXO1.

'We shouldn't treat cancers based on what tissue they come from, but based on the landscape of the genetic mutations present in the tumours,' said Professor Moldovan. 'That's the future of cancer treatment.'