Blocking a new drug target for thrombosis and cancer makes overreaction to immune stress more likely

What is it about?

Upon stimulation of cells, specialized molecules inside cells trigger the cell to respond. One of these - called PI3K-C2α - has recently emerged as a possible new target for blood clot and breast cancer treatment. This means that medicines could be made to block this enzyme. But we still don’t know much about what PI3K-C2α does in our body. In order to find out, we made mice in which we can disable the gene for PI3K-C2α at will. We discovered that, while embryos cannot live without PI3K-C2α, its inactivation in healthy adult mice does not lead to any detectable problems. Things changed when these mice are exposed to a substance that mimics a serious infection: mice without the active enzyme react too strongly and don’t survive, while those with the working enzyme recover. We found that the cells lining our blood vessels play a big role in this effect. This harmful reaction can be stopped by blocking certain signals known to induce cell death. This means that PI3K-C2α is linked to natural processes by which cells die, an important basic science discovery.

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Photo by David Clode on Unsplash

Photo by David Clode on Unsplash

Why is it important?

Add an explanation of what is unique and/or timely about your work, and the difference it might make to help increase readership. Thromboses cause heart attacks and stroke, common causes of death. Blocking PI3K-C2α was recently shown to help prevent dangerous blood clots without affecting normal blood clotting, making this a very promising option for new treatments. We have used a drug-like approach to block PI3K-C2α in mice and studied what happens in the body. Healthy adult mice tolerate this very well, which suggests that drugs targeting this PI3K-C2α could be safe. But when we tested it in a model of severe infection, we saw that blocking the enzyme made the mice much more sensitive, even leading to death. This means we need to be cautious and closely watch how the body responds to bacterial infections when considering this as a treatment. From a basic science perspective, our findings break new ground by revealing a connection between PI3K-C2α and controlled cell death, a process of key relevance for immune responses and inflammation. Further investigation is required to understand how turning off PI3K-C2α makes cells more sensitive to a severe infection challenge.

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