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Pioneering cancer drugs could treat many more patients – by targeting new gene defect

PARP inhibitors were designed as the first treatments to specifically attack cancers such as breast and ovarian in patients with inherited BRCA mutations – but new research finds they can also be effective in cancers with other types of genetic fault.

The research, published in Cancer Research, could broaden out the current clinical trials of PARP inhibitors, giving more patients access to a treatment with significantly fewer side-effects than conventional chemotherapy.

Scientists at The Institute of Cancer Research, London, found that cancers with mutations to a gene called CDK12 were particularly sensitive to PARP inhibitors – drugs which exploit weaknesses in a tumour’s systems for repairing DNA.

Their study - funded by Breakthrough Breast Cancer, Cancer Research UK, the American Association of Cancer Research and the European Union - screened every single gene in the genomes of cancer cells to assess how they influenced the response to the drugs.

Patients with high-grade, or advanced, ovarian cancer are particularly likely to benefit from PARP inhibitors because mutations in the CDK12 gene are found in a significant proportion of patients, but the mutation also occurs in subsets of patients with other cancers.

The new findings could lead to patients having their tumours tested for the CDK12 mutation, to select those eligible for clinical trials with PARP inhibitors. At the moment, most patients enrolled onto trials of the drugs have inherited BRCA mutations.

The scientists screened all 25,000 genes in the genomes of a range of cancer cells with an advanced type of genetic experiment using short hairpin RNA (shRNA) to ‘silence’ every gene one by one. They then treated cells with the PARP inhibitor olaparib to see if silencing particular genes made cells more responsive to the treatment.

They linked the CDK12 gene for the first time with sensitivity to PARP inhibitors in the cell screen, and confirmed in mice that low levels of the CDK12 protein made tumours more sensitive to olaparib. They also found a handful of other ‘hits’ on their screen already known to confer sensitivity to olaparib, including BRCA1.

Study co-leader Dr Chris Lord, Senior Staff Scientist at The Institute of Cancer Research, London, said: “Our study showed that if a cancer has a defect in the CDK12 gene, it is more sensitive to treatment with PARP inhibitor drugs. We’re now keen to see ongoing and future clinical trials of PARP inhibitors include a CDK12 test to their standard range of assessments, in order to test our results in the clinic.

“If our results are borne out in clinical trials, they could have a substantial impact on the number of people who are able to benefit from PARP inhibitors in the future.”

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