BRCA1 and BRCA2, or the so-called “breast cancer genes”, are responsible for about 10 percent of breast cancer cases and 15 percent of ovarian cancers. A special class of drugs was designed to target them, PARP inhibitors, and while initial results were optimistic, in time their effectiveness hasn’t lived up to their expectations. They shrink the tumors, but the disease often returns, more aggressive and difficult to treat.
“Women treated with PARP inhibitors typically go into remission relatively quickly, but a lot of these cancers then become resistant partly because there are other proteins in the cell that can compensate for the lack of BRCA”, explained Andrea Byrum, study’s co-first author. “If we target these other factors, we might be able to make the tumor sensitive to these drugs again”.
Under normal conditions, BRCA genes help repair DNA breaks that can lead to cancer and the uncontrolled growth of tumors. PARP inhibitors knock out another arm of the cell’s DNA repair system, so for people that have BRCA mutations the cancerous cells cannot survive and die.
However, the human DNA repair system is more complex and certain tumor cells with nonfunctioning BRCA genes are capable of restoring BRCA function by boosting another aspect of the system. The team identified a complex of the proteins TPX2 and Aurora A that could mimic the effects of the BRCA proteins.
“If you lose this complex, it’s like you lose BRCA”, noted Nima Mosammaparast, MD, Ph.D., assistant professor of pathology and immunology and senior author. “The nice thing is that there are inhibitors to Aurora A already in clinical trials for other types of cancer such as lymphoma and melanoma. We could combine an Aurora inhibitor and a PARP inhibitor to more effectively target these cancers”.
Researchers noticed that that cells required both the complex and BRCA proteins to optimally protect their DNA as they are dividing. By treating human cells with a DNA-damaging chemical and measuring the lengths of replicating DNA strands, they could see if the cell could in fact regenerate.
“We weren’t looking for a drug when we started this study”, Mosammaparast said. “We were just asking a very basic question about how other genes regulate BRCA, and we stumbled across a potential drug target”.
Finding this vulnerability with BRCA could open the way for improved treatments that prevent cancer resistance and save countless lives.
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