Targeted therapies are a powerful weapon against skin cancer, but their side effects can severely impact a patient’s quality of life. A new study shows that some targeted therapies manipulate signaling events in cells that line blood vessels and result in a weaker vascular barrier. This knowledge sheds some light on possible mechanisms leading to side effects and it can contribute to the development of better therapies for skin cancer. The study was conducted by Sophie Bromberger and colleagues at the Department of Dermatology of the Medical University of Vienna and was recently published in the peer-reviewed scientific journal "Life Science Alliance".
Melanoma is an aggressive form of skin cancer primarily caused by UV radiation. Early detection of suspiciously pigmented skin areas can lead to a good prognosis for patients. However, if left untreated, melanoma can quickly spread to other organs, making it extremely challenging to treat. The current treatment regimen of late-stage melanoma includes so-called "targeted therapies" that deactivate a protein named BRAF, which is often overactivated in melanoma cells. These therapies, known as BRAF inhibitors, can significantly slow down cancer progression in patients. However, they also affect healthy cells, which can lead to side effects like rashes, diarrhea, and vascular issues like swelling and bleeding. This study investigated the molecular and functional effects of targeted therapies on the innermost layer of blood vessels.
Side effects on blood vessels
The research group used cutting-edge mass spectrometry to analyze molecular changes in over 7,000 proteins from vascular cells that were treated with different classes of BRAF inhibitors. The researchers discovered changes in molecular signaling events in these cells and saw surprising differences between the individual BRAF inhibitors, that are supposedly targeting the same protein. Furthermore, one of the BRAF inhibitors, which is rarely prescribed in clinics nowadays, drastically reduced the barrier stability of vascular cells in culture. A disrupted vascular barrier can lead to fluid accumulation in the surrounding organ, which causes side effects and reduces treatment efficiency. A weakened vascular barrier also makes it easier for cancer cells to spread to other organs via the circulation.This study highlights that targeted therapies against skin cancer can actually have substantial effects on healthy cells of human blood vessels. By understanding these effects, future therapies can be designed and applied to minimize unwanted side effects while maintaining their effectiveness against cancer.
The initiative is funded by charitable donations from the Cancer Research Run. Since 2007, donations from the Cancer Research Run have supported over 60 scientific projects working on innovative cancer diagnosis and treatment approaches. The next Cancer Research Run will take place on October 5, 2024.
Publication: Life Science Alliance
Off-targets of BRAF inhibitors disrupt endothelial signaling and vascular barrier function.Sophie Bromberger, Yuliia Zadorozhna, Julia Maria Ressler, Silvio Holzner, Arkadiusz Nawrocki, Nina Zila, Alexander Springer, Martin Røssel Larsen, Klaudia Schossleitner
https://doi.org/10.26508/lsa.202402671
