Breast cancer discovery could help predict treatment resistance

A protein that helps cancer cells divide could offer an early warning that widely used breast cancer drugs are losing their effect.

Researchers found that higher activity of CDK1, a protein involved in cell division, was associated with more aggressive cancers and poorer patient outcomes.

The findings could eventually help doctors identify which patients may benefit from treatment and detect when the drugs are no longer working.

The research, led by the Garvan Institute of Medical Research, focused on oestrogen receptor-positive (ER+) breast cancer, the most common type of the disease, which is fuelled by oestrogen.

Many patients receive CDK4/6 inhibitors alongside hormone therapy. These drugs stop cancer cells from multiplying, but they do not work for everyone and eventually stop working for most patients with advanced disease.

“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,” said 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.”

CDK1, CDK4 and CDK6 belong to a family of proteins that control cell division.

CDK4 and CDK6 help start the process, while CDK1 is needed for the final stage, when a cell splits into two. Cancer develops when normal cell division becomes uncontrolled.

Caldon explained: “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 track CDK1 as breast tumours develop, researchers created a preclinical model with a fluorescent sensor that lights up when the protein is active.

They found that CDK1 activity increased as tumours became invasive.

“Most tests can tell you whether a protein is there, but not whether it’s actually working,” said 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.”

The team also examined breast cancer biopsy samples from more than 400 patients.

Higher CDK1 activity was linked to more aggressive cancers and worse patient outcomes.

Researchers then analysed existing clinical trial data from patients treated with CDK4/6 inhibitors.

In tumours that did not respond, genes for CDK1 and its partner proteins remained active, providing an indirect indication that CDK1 was still involved in driving cell division.

Similar activity was found in advanced cancers that had grown back despite treatment.

Laboratory-grown breast cancer cells also showed renewed CDK1 activity after being exposed to a CDK4/6 inhibitor for around 10 months, until they developed resistance.

In the preclinical model, tumours that continued growing despite treatment had 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,” said professor Paul Timpson, co-senior author and co-director of Garvan’s Cancer Ecosystems Program.

Dr Sarah Alexandrou, first author of the study, said: “CDK1 kept turning up as a red flag – in early breast cancer, in advanced cancer and in cancers that had overcome treatment.

“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.”

The findings build on research conducted at Garvan during the 1990s showing how cyclin D1, a related protein, drives breast cancer growth.

That earlier work helped make the case for developing CDK4/6 inhibitors.

“Finding better options for people whose cancer stops responding to treatment takes long-term commitment,” said 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 findings need to be tested in larger groups of patients receiving CDK4/6 inhibitors before CDK1 activity could be used to guide treatment decisions.

Researchers also believe CDK1 could eventually become a target for new drugs aimed at overcoming resistance.

“Decades ago, CDK4/6 inhibitors were just an idea – now they’re helping people with breast cancer around the world,” said Timpson.

“There’s no drug for CDK1 yet, but that doesn’t mean there won’t be one day.”