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Drug target identified for chemotherapy-resistant ovarian and breast cancer

People who inherit a faulty copy of the so-called "breast cancer genes" - BRCA1 and BRCA2 are at high risk of cancer.

About 10 percent of breast cancer cases and 15 percent of ovarian cancers can be traced back to a flaw in one of these genes.

A class of drugs known as PARP inhibitors were designed to target tumours with defective BRCA genes.

Sold under brand names such as Lynparza, Rubraca and Talzenna, the drugs offered new hope to people with ovarian or breast cancer.

But in the five years since the first one was approved, PARP inhibitors have not lived up to their promise.

Tumours typically shrink when first hit with a PARP inhibitor, but they soon become resistant and enable the cancer to return.

Now, researchers may have found a path toward improving the effectiveness of chemotherapy in people with breast or ovarian cancer that is caused by BRCA defects.

Researchers identified a pair of genes that operate in parallel to BRCA.

Knocking down the genes increases the susceptibility of tumour cells when in contact with toxic chemicals - and potentially to other chemotherapy drugs as well.

"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," said Andrea Byrum, the study's co-first author. "If we target these other factors, we might be able to make the tumour sensitive to these drugs again."

These findings can be found in the Journal of Cell Biology.

BRCA helps repair damaged DNA and fends off the errors that threaten to transform normal cells into cancer cells.

When a person has a BRCA gene that isn't working properly, his or her cells struggle to heal injuries to their DNA.

PARP inhibitors knock out another arm of the cell's DNA repair system.

Together, a flawed BRCA gene and a PARP inhibitor leave tumour cells with a fatal inability to fix DNA damage, which consequently causes the cells to die.

But the DNA repair system is complex and redundant and some tumour cells with non-functioning BRCA genes are able to effectively restore BRCA function by boosting another aspect of the system. 

However, the researchers have found a way to make tumour cells that contain BRCA act like they don't so they can be killed more easily.

Their findings point the way toward making resistant tumour cells susceptible to PARP inhibitors once again.

The team found that a complex of the proteins TPX2 and Aurora A could mimic the effects of the BRCA proteins.

"If you lose this complex, it's like you lose BRCA," said Mosammaparast, the study's 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. I am working on getting funding to do such a study."

Moreover, the researchers found that cells needed both the complex and BRCA proteins to optimally protect their DNA as the cells are dividing.

Co-senior author, Alessandro Vindigni and co-first author Denisse Carvajal-Maldonado, treated human cells with a DNA-damaging chemical and measured the lengths of replicating DNA strands.

The strands were short if either the complex or BRCA was missing and their length was an indicator that the cell was failing to protect its DNA.

"If you don't have BRCA and you inhibit this complex, it could be potentially catastrophic for the tumour," Mosammaparast said.

Defective BRCA genes raise the risk of not just breast and ovarian cancer, but prostate and pancreatic cancers as well.

Finding a way to prevent resistance or restore sensitivity to PARP inhibitors could improve therapy options for many people.

"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. My own personal take on it is that sometimes asking very basic questions leads you to discoveries that you weren't even thinking about."

Source: Washington University School of Medicine



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