Wee1 inhibitors are a promising new cancer treatment, but serious side effects threaten their adoption in the clinic. Now, researchers from the MRC Laboratory of Medical Sciences (LMS), the University of Oxford, and UCL have discovered a previously unknown role for Wee1 that could explain these effects. The findings could realign the drugs' clinical progress, helping to identify patients most likely to benefit from treatment and guiding the development of safer, more targeted therapies.
Toxic side effects are derailing a promising group of clinical trials using Wee1 inhibitors in cancer patients. A study published in Nature, resulting from an interdisciplinary combination of mathematical modelling and lab experiments, might explain these wayward effects and point the way to improving outcomes or better identification of patient populations who could benefit the most.
Cells have several safeguards to stop DNA damage leading to cancer. One of the most important is the tumour-suppressor protein, p53, which can halt the cell cycle when DNA damage is detected. However, p53 is inactive in around half of all cancers, allowing damaged cells to continue growing. Wee1 forms part of a second line of defence, acting as a back-up brake that prevents DNA-damaged cells from entering cell division. Because p53-mutated cancers rely on this remaining safeguard, Wee1 has become a promising drug target. Researchers have now shown that, in addition to this established role, Wee1 also has a previously unappreciated role earlier in the cell cycle in healthy cells.
"Wee1 has been very intensely studied in the later stages of the cell cycle, where targeting its activity for cancer treatment makes sense," says Alexis, Head of the Cell Cycle Control group at the LMS. "However, the side effects of Wee1 inhibitors in patients were hard to explain based on these functions so we started to wonder if this Wee1 enzyme had some other function that we hadn't appreciated that could explain these. We wanted to look earlier in the cell cycle to see if there was something we had missed."
Taking action early
The team set out to interrogate the established understanding of Wee1's role in early cell cycle stages by constructing a mathematical model that predicts the impact of inhibiting Wee1. But when the team tested the model's predictions in healthy and cancerous cells, it became clear that the image of Wee1's activity as painted by the scientific literature was wrong. Alexis says, "we quickly found out that the model we had based on the literature on Wee1 was wrong because that was not what we saw in cells. What had been missed was an early function of Wee1 that people hadn't looked at."
In healthy cells, a protein degradation complex prevents DNA replication from starting by breaking down molecules needed for the process. Wee1 helps switch off this complex early in the cell cycle, allowing DNA replication to begin. Without Wee1, the protein degradation complex remains active, delaying or preventing cells from progressing through the cell cycle.
"We think what's happening in patients is that when they're being treated with these Wee1 inhibitors, it's stopping their normal fast proliferating cells, like you get in the colon and the blood system, from starting to replicate," says Alexis. "And so those cells are stuck, unable to generate new cells, and that could be causing some of the toxic side effects."
More effective treatment for those who might benefit the most
If the side effects are linked to Wee1's role with the protein degradation complex, the researchers suggest that cancers with reduced activity of this complex may be particularly susceptible to Wee1 inhibitors. This could create a therapeutic window in which lower doses of the treatment could kill cancer cells while minimising damage to healthy cells and reducing side effects.
Another approach could be to target Wee1 more selectively. "We're also starting to think about if there are different ways we could inhibit Wee1 that get round this early cell cycle function," says Alexis, "though how this might be achieved is a work in progress."
Refining clinical trials, improving cancer treatments
It was a surprise to discover such a fundamental role of a drug target that has been so thoroughly interrogated en route to clinical trial. "Now we've uncovered this new function for Wee1, are there other functions that we haven't appreciated? What else is it doing that we have not seen since we've not looked at the right stage?" asks Alexis.
Another pressing goal is to further test the predictions of this work in pre-clinical models and in patients currently enrolled in Wee1 inhibitor clinical trials. Bringing this new understanding into ongoing clinical trials could transform the prospects for Wee1 inhibitors, helping to overcome the side effects threatening their development and offering new hope to patients.
This work was part of a collaboration between the LMS, Hiro Yamano at UCL and the late Béla Novák of the University of Oxford.
This study was funded by the Medical Research Council and Cancer Research UK.
