17 January 2022

Blood cancer patients whose disease carries a specific gene defect could be treated with existing drugs, according to a new study led by UK researchers, which they believe could have “huge implications” for outcomes and quality of life.

Mutations in the SF3B1 gene are most often found in blood cancers, such as chronic lymphocytic leukaemia and myelodysplastic syndromes, as well as in some rare cancers including uveal melanoma.

Now scientists at Queen’s University Belfast and the University of Birmingham say SF3B1-mutated tumours respond to PARP inhibitors and etoposide.

The research, published in the latest edition of Cancer Research, found the SF3B1 mutation produces similar effects to the faulty BRCA1 gene: it damages DNA, prevents it from being repaired properly and blocks it from making normal copies of itself.

However, PARP inhibitors target the cell’s DNA repair tools by locking them in place on the DNA, which stops DNA repair and results in the death of the cancer cells.

Lead author Dr Kienan Savage, reader at the Patrick G Johnson Centre for Cancer Research at Queen’s, said: “Our findings have clinical implications for the treatment of many cancers. We specifically focused on this genetic mutation as it is found in several difficult to treat leukaemias and other cancers, and it affects so many cancer patients.

“By deepening our understanding of this gene mutation, we have identified new ways of treating these cancers that could improve survival rates.”

Cancer cells with the SF3B1 mutation were found to be sensitive to olaparib, the most common PARP inhibitor, some specific chemotherapies and to radiotherapy. The researchers believe the SF3B1 mutation disrupts the cell’s ability to make DNA repair proteins, which then leaves it vulnerable to drugs that target these proteins.

First author Dr Katrina Lappin, from Queen’s, added: “Our research shows that cancers with these specific mutations, may be treated effectively with PARP inhibitor therapy drugs, which are less toxic, better at killing cancer cells with these mutations and can be taken at home in tablet form. This could have huge implications for improving outcomes and quality of life of people with these cancers.”

The researchers want to test PARP inhibitors in clinical trials with patients who have the SF3B1 mutation, to see if they can stop their cancer from spreading.

Co-author Professor Grant Stewart, of the University of Birmingham, said: “Our work demonstrates that a molecular understanding of how a specific gene mutation affects a cancer cell’s ability to repair damaged DNA can be exploited clinically to specifically tailor the anti-cancer therapy used to treat an individual’s tumour. This will increase the effectiveness of the therapy and hopefully, reduce the chances of re-occurrence.”

Michelle Mitchell, chief executive of Cancer Research UK which helped to fund the study, added: “It’s really exciting to hear about a new mutation, which behaves like the BRCA1 mutation and could in the future be treated in the same way. With PARP inhibitors already widely available, there is huge potential to help people with some of the rarest and most difficult-to-treat cancers known to us.”

Source:

Lappin KM, Barros EM, Jhuh SJ, Irwin GW, McMillan H, Liberante FG, Latimer C, La Bonte MJ, Mills KI, Harkin DP, Stewart GS, Savage KI. (2022) “Cancer-associated SF3B1 mutations confer a BRCA-like cellular phenotype and synthetic lethality to PARP inhibitors.” Cancer Research, doi: 10.1158/0008-5472.CAN-21-1843

Link: https://cancerres.aacrjournals.org/content/early/2022/01/11/0008-5472.CAN-21-1843

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