Protein offers clues to which breast cancers will resist targeted therapy

Researchers at the Garvan Institute of Medical Research have discovered that the activity of a protein called CDK1 in breast cancers is linked to how they respond to a common therapy – an insight that could inform more personalised treatment approaches for patients.

The study, published in Advanced Science, looked at estrogen receptor-positive (ER+) breast cancer – the most common type, fuelled by the hormone estrogen. Many people with this cancer now receive drugs called CDK4/6 inhibitors alongside hormone therapy. These drugs stop cancer cells from multiplying, but they don’t work for everyone, and in advanced cancer eventually stop working for most patients.

“CDK4/6 inhibitors have made a real difference for people with breast cancer, but right now we can’t tell who will get the most out of them, or whether they’ve stopped working,” says Associate Professor Liz Caldon, Lab Head at Garvan and co-senior author of the study. “We wanted to find a signal in the tumour itself that tells us who is most likely to benefit and whether the therapy is doing its job.”

Is the engine on?

CDK1 belongs to the same family of proteins as CDK4 and CDK6, which control when cells divide. CDK4 and CDK6 set the process in motion, while CDK1 is needed for the final stage, when the cell splits in two. Healthy cells divide this way – cancer is what happens when that process runs out of control. 

Associate Professor Caldon explains: “CDK1 is like the ‘engine’ that has to start for a cell to divide. CDK4/6 inhibitors work by jamming the cell’s ignition, but some cancer cells find a way to ‘hotwire’ around it. Even then, the cell can only divide if the CDK1 engine is running – so checking whether it’s switched on shows whether the drugs are still holding the cancer back.”

To follow CDK1 as breast tumours grow, the team developed a new preclinical model carrying a fluorescent sensor that lights up whenever the protein is active. Using it, they found CDK1 activity rose as tumours became invasive.

“Most tests can tell you whether a protein is there, but not whether it’s actually working,” says Dr Max Nobis, co-senior author of the study, now a lab head and lecturer at the University of Manchester. “This model shows us which cells have CDK1 switched on, so we can track the cell cycle being activated during treatment.”

In more than 400 patients’ breast cancer biopsy samples, the researchers also found CDK1 activity rose as the cancer became more aggressive, and higher activity was linked to worse outcomes.

Spotting cancers that become resistant

The researchers then used existing clinical trial data to investigate breast cancers that had been treated with CDK4/6 inhibitors. In tumours that didn’t respond, the genes for CDK1 and its partner proteins stayed switched on – an indirect sign the CDK1 engine was still running. The same activity appeared in advanced cancers that grew back despite treatment.

Breast cancer cells grown in the lab with a CDK4/6 inhibitor for around 10 months, until they became resistant, had also restarted their CDK1 engine, and in the preclinical model, tumours that kept growing despite treatment showed higher CDK1 activity.

“It can take only a small number of surviving cells to bring a cancer back, so being able to see which ones are still active gives us a new view of how treatment resistance starts,” says Professor Paul Timpson, co-senior author and Co-Director of Garvan’s Cancer Ecosystems Program.

“CDK1 kept turning up as a red flag – in early breast cancer, in advanced cancer and in cancers that had overcome treatment,” says Dr Sarah Alexandrou, first author of the study. “If a tumour has high CDK1, that may be a sign CDK4/6 inhibitors won’t work as well, which is something doctors could one day use when planning each patient’s care.”

Building on decades of Garvan research

The work follows Garvan research in the 1990s showing how a related protein, cyclin D1, drives breast cancer growth – findings that helped make the case for CDK4/6 inhibitors years before they reached patients.

“Finding better options for people whose cancer stops responding to treatment takes long-term commitment,” says Associate Professor Caldon. “Over many years, our lab has built a collection of breast cancer cells that have become resistant to different drugs, and each one takes many months of careful work. These models are where we saw CDK1 switching back on, and our hope is that tracking CDK1 will help doctors match each person with the treatment most likely to work for them.”

The team says the findings now need to be tested in larger groups of patients treated with CDK4/6 inhibitors, and could eventually open the door to new drugs targeting CDK1.

“Decades ago, CDK4/6 inhibitors were just an idea – now they’re helping people with breast cancer around the world,” says Professor Timpson. “There’s no drug for CDK1 yet, but that doesn’t mean there won’t be one day.”

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The research was a collaboration with UNSW Sydney, St Vincent’s Hospital Sydney, NSW Health Pathology, the University of Manchester and the Cancer Research UK Scotland Institute. It was supported by the National Health and Medical Research Council; Love Your Sister in Association with the National Breast Cancer Foundation, Australia; the Cancer Institute NSW; Cancer Research UK; the St Vincent’s Clinic Foundation; an Australian Government Research Training Program Scholarship; Kedje Foundation; Mostyn Family Foundation and the Lysia O’Keefe Fellowship.

Dr Sarah Alexandrou is a Conjoint Lecturer at the School of Clinical Medicine, UNSW Medicine and Health. Professor Paul Timpson is a Conjoint Professor at the School of Clinical Medicine, UNSW Medicine and Health. Dr Max Nobis is a Lecturer at the School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, UK. Associate Professor Liz Caldon is a Conjoint Associate Professor at the School of Clinical Medicine, UNSW Medicine and Health.