PARP inhibitors can be blocked in cancer treatment by the p97 protein, but this in turn can be blocked by a repurposed drug Disulfiram, increasing the number of people with BRCA1/2 mutations who may derive benefit with their breast, prostate, ovarian and pancreatic cancers.
PARP inhibitors like olaparib, talazoparib and rucaparib are clever drugs used to treat some patients with ovarian, breast, prostate and pancreatic cancers – usually patients who have inherited a faulty BRCA1 or BRCA2 gene. They work by targeting PARP1. It’s one of the cancer cells’ DNA repair proteins. By blocking it and trapping it on the cancer cell surface this causes cancer cell death.
However, the drugs don’t work in about 40% of patients. Professor Chris Lord and his team at The Institute of Cancer Research (ICR) discovered this was due simply to cancer cells kicking this repair protein (PARP1) off their surface when under attack from the PARP inhibitor.
In their studies with BRCA1 breast cancer, they found a protein p97, which could initiate the shedding, so they attempted to block that and found that a repurposed drug Disulfiram, normally used to treat alcohol addiction, could block p97.
For example, a 1nM dose of talazoparib killed about 30% of the cancer model, but that increased to 90 per cent when used with disulfiram to inhibit p97.
Obviously more work is needed, but it’s a very important discovery.
Go to: BRCA1 and BRCA2 mutations and PARP inhibitors
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Reference
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Study uncovers how cancers resist targeted treatment - Institute of Cancer Research; Jan 10th 2022 - https://www.icr.ac.uk/news-archive/study-uncovers-how-cancers-resist-targeted-treatment