WEHI researchers have found a new way to predict a subset of patients who are likely to become resistant to PARP inhibitors (PARPi), a key therapy used to treat ovarian and breast cancers in Australia.

Using patient blood samples, the research team has been able to detect, for the first time, a specific process that can make ovarian cancer cells resistant to PARPi treatment – a significant finding that could enable the early detection of patients who won’t respond well to the therapy.  

Medical researchers can immediately start to look for this form of resistance using tests that are currently being used in research settings and soon clinicians will be able to order these tests.

The breakthrough will improve patient care and potentially lead to clinical trials focused on overcoming drug resistance. It is anticipated that testing for this type of resistance, using a straightforward blood test, will eventually become a standard practice in both clinical and research environments.

At a glance

• WEHI-led study finds new way to predict a subset of ovarian cancer patients who will become resistant to PARP inhibitors – a therapy used for many ovarian and breast cancer patients.
• For the first time, researchers were able to detect altered gene 'splicing' (a process that can make cancer cells resistant to PARPi therapy) in the blood.
• The findings can be immediately applied to tests already available in research settings, such as DNA sequencing of a patient's tumour or detecting cancer DNA in the blood.

More than 1700 women are diagnosed with ovarian cancer and over 20,000 people are diagnosed with breast cancer in Australia every year.

PARPi therapy has been a breakthrough for treating ovarian and breast cancers. In high-income countries, most patients with a DNA repair deficiency known as HRD – which can be caused by BRCA1 or BRCA2mutations – are now receiving this treatment. 

However, drug resistance remains a major challenge in PARPi therapy, with the majority of patients eventually experiencing relapse.  

The process of splicing can cause cancer cells with mutations in genes, such as BRCA1, to become resistant to PARPi treatment.

This means cancer cells with mutated BRCA1 genes can 'skip over' the mutation that the drug exploits, removing the drug vulnerability and causing the cancer to become resistant. 

A new WEHI-led study has been able to detect DNA changes that cause this ‘splicing trick’ in the blood for the first time.

Co-first author and WEHI ovarian cancer researcher Dr Ksenija Nesic said the findings solve a long-standing ‘blind spot’ in cancer research and could mark a turning point for cancer treatment. 

“It’s been known for a while that splicing creates drug resistance. What we didn’t know was how the cancer cells do this and whether we could detect, measure and predict it in patients,” Dr Nesic said.

The findings show, for the first time, that this form of drug resistance can be detected in a subset of ovarian cancer patients through a blood test, or by examining the patient’s tumour itself.

Specifically, the study identified this drug resistance in ovarian cancer patients who have mutations in the BRCA1 gene.

“This could be transformative for the cohort of ovarian cancer patients who have mutations in the BRCA1 gene, and potentially for other ovarian cancer patients too,” Dr Nesic said.

“We are hopeful that further research will reveal similar splicing mechanisms in BRCA2 and other genes that relate to HRD.”

HRD (homologous recombination deficiency) is found in approximately 50% of ovarian cancer patients.

Among these patients, about half have mutations in the BRCA1 or BRCA2 genes.

“The findings could revolutionise patient care, as doctors will now know they can look for splicing changes and more importantly, how to look,” Dr Nesic said.

Existing tests that show these changes are currently being used in research settings.

These include DNA sequencing of a patient's tumour or detecting cancer DNA in the blood. Soon clinicians will be able to order these tests directly and look out for this form of resistance.

It is hoped that testing for this type of resistance, in the form of a simple blood test, will eventually become standard practise in clinical as well as research settings.

“The discovery is profound because it opens up an avenue to monitor for drug resistance, where clinicians can in the future easily detect altered splicing of genes for BRCA1 and potentially for other genes involved in HRD, as their patient stops responding to therapy,” Dr Nesic said. 

“While there are many types of resistance to PARP inhibitors, being able to identify those patients who are no longer going to respond to PARPi treatment early, enables better decision-making – meaning patients can be moved onto the next best therapy.

“The ultimate goal is to stop drug resistance in its tracks, for PARPi and for other types of drug resistance too. This research brings us closer to achieving this.”

Big leap for personalised treatment

The identification of the splicing mechanism offers a non-invasive method for monitoring PARPi resistance, potentially predicting this type of resistance. Importantly, it allows for early detection and better tailoring of cancer therapies for individual patients.

Senior co-author and cancer genetics specialist Associate Professor Matthew Wakefield said the findings could be revolutionary for ovarian cancer patients with an HRD gene mutation, currently being treated with PARPi therapy.

“Cancers becoming resistant to therapy is a big issue with targeted drugs like PARP inhibitors,” Assoc Prof Wakefield said.

“Being able to spot drug resistance early with a blood test, and switch to another treatment to avoid the resistance, will allow people to continue to control their cancer more successfully.

“It is a significant finding that will help patients stay healthier for longer.”

Senior co-author and head of WEHI’s Ovarian and Rare Cancer Laboratory, Professor Clare Scott, said that the team hopes to find ways to prevent this type of resistance as research advances in this space.

“Discovering how to prevent this type of resistance, before it even happens, would be another valuable step towards curing ovarian cancer,” she said.

Prof Scott said the team’s next focus will involve developing drugs to target splicing mechanisms and exploring other genes involved in similar resistance pathways.

“In future, we hope to discover a drug that can prevent the splicing from occurring or stop it when it does occur,” she said. “We’d offer this to patients alongside their treatment to enhance early intervention and patient care for women facing the challenges of gynaecological cancers.”

The study involved collaborations with the Fox Chase Cancer Centre (Philadelphia, USA), Clovis Oncology (USA), Royal Women’s Hospital, Peter MacCallum Cancer Centre (Peter Mac), Australian Ovarian Cancer Study and was funded by the Stafford Fox Medical Research Foundation. Dr Nesic was also supported by an AACR-AstraZeneca Ovarian Cancer Research Fellowship during this work.

The research team studied cancer samples donated to the WEHI-Stafford Fox Rare Cancer program and blood samples collected as part of a large international clinical trial.

The study, “BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance”, is published in Molecular Cancer .

Source: Walter and Eliza Hall Institute