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Cancer with mutations in the SF3B1 gene on PARP inhibitors-a type of drug used to treat cancer with mutations in the BRCA1 and BRCA2 genes, scientists at Queen's University Belfast and the University of Birmingham report in a paper published on January 13, in "Cancer-Associated SF3B1 Mutations Confer a BRCA-Like Cell Phenotype and PARP Inhibitor Synthetic Lethality" in the journal Cancer Research
Mutations in the gene SF3B1—particularly K700E, which substitute glutamate for lysine (K) (E), the 700th residue of the gene—have been found in several types of cancers including blood cancers such as myelodysplastic syndromes, chronic Lymphocytic leukemia, and some rare cancers such as uveal melanoma, cancer
SF3B1 is a key component of a multi-protein complex called the spliceosome, which connects the protein-coding segments of thousands of genes, including those that respond to DNA damage in cells
In cell line and animal studies, the team found that tumors with the SF3B1-k700e mutation responded to drugs that inhibit poly ADP ribose polymerase (PARP) and could therefore be used to treat patients with tumors that carry a defective SF3B1 gene
The authors show that the mutation leading to SF3B1 deletion is epistatic to BRCA1 deletion, suggesting that the cellular effects of SF3B1 mutations are dependent on the presence of BRCA1 mutations
Savage and his team found that cancer-associated mutations in SF3B1 produce a brca-like cellular phenotype that damages DNA, prevents DNA repair, and prevents DNA from normal self-replication
"Our research suggests that cancers with these specific mutations may be effectively treated with PARP inhibitor therapy drugs that are less toxic and more effective at killing cancer cells with these mutations and can be administered at home as a tablet
Lappin added: "This work will pave the way for clinical trials of PARP inhibitors in patients with this often associated cancer mutation, allowing for more personalized treatment of these cancers
Dr Grant Stewart, Professor at the University of Birmingham and the paper's senior author, said: "Our work shows that molecular understanding of how specific genetic mutations affect the ability of cancer cells to repair damaged DNA can be exploited in the clinic, specifically tailored for use in Anticancer therapy to treat individual tumors
"It's really exciting to hear about a new mutation that behaves like a BRCA1 mutation and may be treated in the same way in the future
The team plans to conduct clinical trials in patients with SF3B1 mutations to test the PARP inhibitor for evidence that it can stop the spread of this type of cancer
