Tim Hunt, the 2001 recipient of the Nobel Prize in Physiology or Medicine, awarded for discovery of the proteins that control cell division, once asked “have you ever wondered how our arms end up being the same length?”.

It’s a great question, and one I think about a lot.

The answer lies in the exquisite coordination and control of cell division. To enable proper tissue development, growth and repair, cells must replicate in the right place, at the right time, to build and maintain wonderfully complex, functional organs. This process is normally very tightly controlled in response to combined chemical and physical signals. The signals that a cell receives will vary, depending on which organ or tissue the cell resides in. To add to this complexity, the cellular signalling pathways triggered by these signals – that will ultimately lead to cell division – are also different, depending on the cell type.

All cancers have dysfunctional cell cycle control, where cells no longer respond to those chemical and physical signals. Of course, the difficulty in trying to stop cancer cells from replicating is that the mechanisms driving cancer cell proliferation are a mutated version of those in non-cancer cells.

So, how can we ensure that we stop cancer while leaving healthy cells alone?

A new dawn – but questions remain

Progression through the cell cycle is driven by cyclin-dependent kinases, or CDKs. These are activated in a specific order – first CDK4 and CDK6, then CDK2 and finally CDK1. CDK7 is also needed to activate these CDKs.

Efforts to target CDK activity for cancer therapy began in the 1990s, with the first generation of cell cycle inhibitors. Drugs such as Seliciclib and Alvocidib inhibited all CDKs. However, clinical trials with these drugs were quickly stopped. Because these drugs targeted a range of different CDKs, their specificity for any one of them was low. A high drug dose was required to achieve an anti-tumour effect which, in turn, caused high levels of toxic side-effects by damaging healthy, replicating cells.

This lack of success halted the launch of new efforts to try and stop cancer cell proliferation for years. However, in the last 15 years, new drugs capable of targeting specific, individual CDKs, have been successful in certain cancers. For example, Palbociclib, Ribociclib and Abemaciclib, that target CDK4 and CDK6, and Samuraciclib, that targets CDK7, are licensed to treat oestrogen receptor-positive (ER+) HER2- metastatic breast cancer and are being trialled in other cancer types. Many CDK2 inhibitors are currently in development. Crucially, these drugs have minimal side-effects on healthy cells. The advent and licensing of new CDK inhibitors demonstrate that specific targeting of cancer cell replication is possible.

The question now is – which patients should be given these drugs? Which tumours will respond?

The many ways of losing control

This is where a huge challenge emerges. While all cancer cells are defined by uncontrolled cell replication, how different cancers lose that control varies. Of the complex network of proteins that coordinate the cell cycle, gain or loss – or a change in the behaviour – of different components can achieve the same result of uncontrolled cell division.

Targeted CDK inhibitors don’t work across all cancer types. We see this where CDK4/6 inhibitors can successfully treat ER+/HER2- metastatic breast cancer but they are significantly less successful in treating other cancer types, even other breast cancers. We don’t fully understand the reasons for this, but one thing we do know is that cancers emerging in different organs, and even different cancers within the same organ, have acquired different genetic changes which drive uncontrolled cell division.

One reason that these differences emerge is because different organs have bespoke cell cycle control mechanisms to regulate their unique development and maintenance. Therefore, a genetic alteration in one cell-type in one organ may drive uncontrolled division and give those cells a growth advantage over its neighbouring cells, but the same genetic alteration may have no effect in a different cell-type or organ.

In the case of ER+ breast cancer, CDK4 activity is vital for those cancer cells to proliferate, and those cancer cells are unable to use an alternative pathway to progress through the cell cycle. Therefore, CDK4/6 inhibitors work well in ER+ disease.

Taking back control

How do we tackle this problem? How do we identify how different cancer cells proliferate and then how do we use that knowledge to stop their proliferation while sparing healthy cells?

There is a wealth of data available describing the genetic, transcriptomic and proteomic changes that occur in different cancers. Together with Maria Secrier at UCL, we want to systematically analyse the alterations that occur in cell cycle control genes in individual cancer types, understand what impact those combined changes have on gene expression programmes and predict what the effect will be on cell division.

This is a significant computational challenge but one that we can tackle. Through close collaboration between computational and experimental scientists, we can test our predictions in model systems in the lab. Building on decades of discovery research to understand how the cell cycle is controlled, we can also identify vulnerabilities in these cancer cell cycle networks – proteins that we can target to specifically halt cancer cell proliferation. This may identify cancers where existing CDK inhibitors will be effective or indeed drive the generation of new drugs targeting other cell cycle proteins.

The success of CDK4/6 inhibitors has given us renewed excitement in targeting the cell cycle in cancer. However, their lack of efficacy in other cancer types has revealed our ignorance in how cancers emerging in different tissues replicate. The Nobel Prize for the discovery of the key regulators of the cell cycle may have been awarded 24 years ago, but we still have some way to go in understanding the complexity of tissue-specific cell cycle control and what that means for restraining cancer cell division.