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Research: Novel protein complex may help predict response to anti-cancer drugs

By Allen Cone
Research: Novel protein complex may help predict response to anti-cancer drugs
researchers have discovered a novel protein complex that could help predict patients' response to new anti-cancer drugs, including ones to treat breast cancer. Photo by CristinaMuraca/Shutterstock

July 25 (UPI) -- Using gene-editing technology, researchers have discovered a novel protein complex that could help predict patients' responses to new anti-cancer drugs.

Scientists at Cambridge University Hospitals in Britain hope tests will prove Shieldin will determine the effectiveness of drugs. Their findings were published this month in the journal Nature Cell Biology.

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The protein, called Shieldin because it shields the ends of broken DNA, regulates DNA repair.

"As we improve our understanding of these DNA repair networks and how they interact, we should be able to better predict the responsiveness of an individual patient's tumor to specific therapies like PARP inhibitors, and ultimately personalize cancer therapy to achieve the maximum benefit," research leader Dr. Steve Jackson said in a press release.

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The researchers had earlier found new class of drugs called PARP inhibitors -- Poly ADP-ribose polymerase -- treated cancers with mutations in the tumor suppressor gene BRCA1. That gene and other related mutations are found in several cancers, including in the breast, ovaries and prostate.

With drug resistance common, the researchers wanted to find out how resistance might develop.

Researchers looked for factors in the human genome that could cause drug resistance in cancer cells that lacked BRCA1.

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They identified two genes that produce the Shieldin complex. They then found Shieldin plays an important role in repairing DNA breaks known as "non-homologous end-joining," or NHEJ. This mechanism essentially "sticks together" the broken DNA strands but can result in deletions of segments of DNA.

They used the Clustered Regularly Interspaced Short Palindromic Repeats tool, which combines a scissor-like protein called Cas9 and a guide molecule that seeks a precise site in the genome. Then, Cas9 snips the DNA, which disables the targeted gene.

"In BRCA1 mutated cells, it appears as though the persistence of the Shieldin complex at DNA breaks renders these cells sensitive to PARP inhibitors," lead author Harveer Dev, urology registrar at Addenbrooke's Hospital, which is among the Cambridge facilities, said. This explains why these drugs are normally effective in patients with BRCA1 mutations. But when Shieldin levels are low, patients can develop resistance to these drugs."

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The researchers, to confirm their results, took breast cancer biopsies from patients with the BRCA1 mutation and transplanted them into mice.

Mice had low levels of Shieldin originally and didn't respond to the PARP inhibitors.

They found that resistance to PARP inhibitors cause some cancer cells to develop vulnerabilities to alternative cancer treatments, including radiotherapy or platinum-based chemotherapy.

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