Researchers at the MRC London Institute of Medical Science (LMS) have shown Palbociclib, a drug used to treat hormone-dependent breast cancer, does not rely on naturally occurring cell cycle inhibitors to stop cells from replicating. 

Palbociclib is currently used to treat hormone-dependent breast cancer. It is also being trialled in other types of cancer. However, research has shown that some cancers can survive Palbociclib treatment. As such, we urgently need to find ways to better identify which cancers will be most susceptible to Palbociclib. This will help to ensure patients are given the treatment most likely to work for them.

One of the barriers to identifying Palbociclib-sensitivity is that we do not understand exactly how the drug stops cancer cells from replicating. Previous research has shown it works through the inhibition of cyclin dependent-kinases (CDKs) – enzymes that are essential for cell growth and division, but exactly how Palbociclib affects CDK activity remains a mystery.

The LMS Cell Cycle Control group are working to gain a better understanding of Palbociclib’s mode of action. This will assist in better identifying patients who will benefit most from the drug. It will also assist in the assessment of which drugs could be used in combination with Palbociclib to prevent cancer cell replication.

Two mechanisms have been put forward for how Palbociclib prevents cell replication. The first is by direct inhibition of CDK4 and CDK6 enzymes to stop them from working. The second mechanism depends on CDK inhibitor proteins, which are naturally found in cells and are known as p21 and p27.

If Palbociclib activity is dependent on p21 and p27, it might be predicted that assessing cancer cells for their p21 and p27 expression could detect whether they would be susceptible to Palbociclib treatment. It was thought that the higher the levels of p21 and p27 the more sensitive the cancer would be. However, the LMS Cell Cycle Control group have used single cell video microscopy and CRISPR techniques to show Palbociclib can still prevent cell replication when cells are depleted of p21 and p27. This suggests these proteins are not essential for Palbociclib to act in cancer cells.

Dr Betheney Pennycook, Postdoc in the Cell Cycle Control Group at the MRC LMS and first author said: “We’re really pleased to share this work. As the potential uses for Palbociclib in the treatment of cancer increase, it is becoming more important for us to understand how it works to stop cell proliferation. This will be vital for the identification of new predictive markers to classify which tumours might be sensitive.”

LMS insights suggest that, contrary to what was previously thought, looking at the levels of p21 and p27 proteins in patient biopsies may not be useful to stratify patients for treatment with Palbociclib, or with other similar CDK4/6 inhibitors.

Dr Alexis Barr, Head of the Cell Cycle Control group at the MRC LMS and corresponding author said: “Breast cancer is the most common cancer in women in the UK. There are currently three clinically approved CDK4/6 inhibitors for the treatment of metastatic hormone-dependent breast cancer, and their use in other cancers is currently being investigated. There are certainly more questions to be answered regarding how these drugs prevent cell replication, but our findings increase the understanding of this class of cancer treatments. This will contribute to the development of more personalised cancer therapies.”

‘Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27’ was first shared as a preprint on BioRxiv in May 2021. It was then published in Open Biology in November 2021. This research was jointly sponsored by the MRC and Cancer Research UK.