CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib, are important medicines for treating hormone receptor (HR) positive breast cancer, especially after tumours have become resistant to endocrine therapy (tamoxifen and/or aromatase inhibitors). (Read more about endocrine therapy here.)
At Breast Cancer Trials’ recent conference in Hobart Dr Shom Goel explained how they work and reported on progress in research and development of other medicines with similar modes of action.
CDK (cyclin dependent kinase) 4/6 inhibitors work by interacting with various proteins involved in normal cell division (the ‘cell cycle’) and slowing down the process when it gets out of control in tumour cells.
Dr Goel described RB (retinoblastoma) protein as one of the key payers in the cell cycle. RB is a tumour suppressor protein; when it binds to a transcription factor called E2F1, cell division is halted. However, when RB is phosphorylated, it releases E2F1 and cell division can commence once again. RB acts as an ‘on/off switch’ for cell division.
“RB phosphorylation is at the heart of the matter” according to Dr Goel. RB’s state is affected by other proteins called cyclins, and their activity is affected by their interactions with cyclin dependent kinases (CDKs). Furthermore, these are influenced by oestrogen receptors, HER2 receptors, various growth factors and their receptors, and other cell signaling pathways such as PI3K/AKT/mTOR and RAS/RAF/MEK/ERK. (See diagram 1.)
Dr Goel described a ‘tug-of-war’ on RB that occurs in HR positive breast cancer tumours. Oestrogen receptors, Cyclins D and E, CDK4/6 and the PI3K/AKT/mTOR pathway are all acting to increase RB phosphorylation (and encourage tumour growth), whereas endocrine therapy and CDK4/6 inhibitors are acting to de-phosphorylate RB (and stop tumour growth). (See diagram 2.) “Unfortunately, if you suppress RB phosphorylation for a long time, the cell always finds a way around it” said Dr Goel.
Other drugs that target this process are being investigated.
Atirmociclib is a CDK4 selective inhibitor, which seems to be more potent and less toxic (less neutropenia) and active in tumours with ESR1 and PIK3CA mutations. It is one of the treatments in the FourLight-3 clinical trial (unfortunately not recruiting in New Zealand). BGB-43395 is another CDK selective inhibitor being researched.
CDK2 inhibitors are also being developed (read more here), INX-315 is one example, tagtociclib is another. Dr Goel suggested that CDK2 might kick in after CDK4/6 inhibition stops CDK4/6 from working, so there could be benefit in inhibiting both, by administering inhibitors to both either at once or in sequence. He also said that there might be value in a ‘triple treatment’ using CDK2 inhibition, CDK4/6 inhibition and endocrine therapy concurrently.
As HR positive breast cancer is the most common sub-type, affecting many women every year, it was encouraging to hear about the global effort being put into researching and developing these new medicines.
13 August 2025
