Inhibiting Wee1 helps kill cancer cells but comes at a cost elsewhere in the body.
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A small protein known as Wee1 plays a significant role in the body’s response to cancer. For years, researchers have investigated drugs that target Wee1 G2 checkpoint kinase (Wee1), aiming to develop treatments that can effectively eliminate cancerous cells. However, clinical trials revealed that patients experienced severe side effects, including diarrhea, vomiting, fatigue, and decreased blood cell counts.
In a recent study, scientists have identified a previously underappreciated function of Wee1 in healthy cells that accounts for these detrimental side effects. The findings, published in Nature, could inform patient selection for therapies involving Wee1 inhibitors.
The Dual Role of Wee1 in Cancer and Healthy Cells
Wee1 functions by inhibiting cyclin-dependent kinase 1 (CDK1), a protein responsible for advancing cells through the cell cycle. This regulatory mechanism is particularly crucial in tumor cells where TP53, another cell-cycle regulator, is mutated. Such tumor cells divide rapidly, creating immense molecular stress. Paradoxically, Wee1 supports these cancer cells by allowing them to pause and repair their DNA before continuing the cell cycle. Inhibiting Wee1 removes this checkpoint, pushing cancer cells into uncontrolled division and eventual death.
However, this promising approach encountered setbacks in clinical trials with drugs like adavosertib. Alexis Barr, a cell biologist at the MRC Laboratory of Medical Sciences and co-author of the study, noted that there was a missing piece in understanding Wee1’s full biological role.
“Wee1 has been extensively studied in later cell cycle stages, where its inhibition shows therapeutic potential,” she explained. “However, the pronounced side effects in patients could not be explained by these known functions alone. We hypothesized that Wee1 might have an additional, overlooked role during earlier cell cycle phases.”
Mathematical Modeling Uncovers New Insights
The research team developed a mathematical model to analyze the impact of Wee1 inhibition during early cell cycle stages. Their model revealed that in healthy cells, a protein degradation complex dismantles key molecules necessary for initiating DNA replication, thereby preventing replication. When cells prepare to replicate, Wee1 intervenes to remove this obstruction. Blocking Wee1 with inhibitors halts DNA replication in healthy cells, particularly affecting tissues requiring rapid cell division, such as the colon and bone marrow. The researchers propose that this mechanism underlies the observed side effects.
Despite these findings, the study offers hope for refining Wee1-based cancer treatments. Certain tumors exhibit reduced levels of the protein degradation complex, potentially making them more responsive to Wee1 inhibitors. By optimizing drug dosages, it may be possible to target cancer cells effectively while minimizing harm to healthy tissues.
Nevertheless, the study highlights a concerning oversight in drug development. Although Wee1 inhibitors were well-characterized before entering clinical trials, this critical cellular function remained undetected. “Our discovery raises new questions about Wee1’s broader roles. What other functions might we have missed simply because we weren’t examining the right cellular context?” Barr reflected.
