Tyrosine kinase inhibitors are a type of targeted cancer medicine that can attack certain types of cancer cells and stop them from multiplying. Although these inhibitors, called TKIs, can be very useful in fighting some types of cancer, they also cause serious inflammatory side effects that limit their use. A Japanese research team has discovered the underlying mechanism that causes this inflammation.
This study revealed the underlying mechanism by which TKIs cause inflammation, thus providing the necessary molecular basis to overcome pro-inflammatory side effects.”
Atsushi Matsuzawa, Professor, Health Chemistry Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University
The team’s results are published in Journal of Immunology On February 6, 2023.
These anticancer drugs are essential anticancer drugs. However, using TKIs too often causes inflammation in the body, such as the lung disease interstitial pneumonitis. From their previous studies, the team learned that a representative TKI called Gefitinib (GF) causes lung inflammation. GF is a useful cancer drug used in the treatment of some types of breast, lung, and other types of cancer. It works by targeting epidermal growth factor receptors. When GF is used to treat cancer, it can cause inflammation in the patient’s lungs, through NLRP3 inflammation. The NLRP3 inflammatory fragment is part of the body’s immune system and plays an important role in innate immunity. But when the inflammasome NLRP3 is improperly activated, it can contribute to the development of a wide variety of inflammatory diseases.
Until now, scientists did not fully understand why the inflammasome activated NLRP3, but evidence seemed to point to mitochondrial dysfunction. When mitochondria are healthy, they function like batteries, producing energy in the body’s cells. Mitochondrial dysfunction occurs when the mitochondria do not work as well as they should due to disease. In their previous study, the team learned that GF activated the NLRP3 inflammatory antibody through mitochondrial damage that led to interstitial pneumonia in patients. However, they did not understand how GF initiates mitochondrial damage and whether or not other TKIs participate in this mechanism.
To conduct their study, the team looked at tyrosine kinases, those enzymes that act as a kind of “on” and “off” switch in many cell functions. They specifically studied the kinases of the Src family, called SFKs. SFKs are non-receptor tyrosine kinases that regulate many cell processes. There are 11 SFKs in the human genome. Some of these SFKs are located in the mitochondria and play an essential role in mitochondrial function. The team found that all of the TKIs they tested inhibited the activity of the SKFs kinase in mitochondria responsible for the NLRP3 inflammatory particle.
The team’s comprehensive analysis of the TKIs they tested showed that the TKIs act as powerful stimulants. In addition, the team noted off-target activity that could contribute to the side effects. “As an important finding, all of the TKIs we tested share a common off-target activity against mitochondrial SFKs. Therefore, blocking access of TKIs to the mitochondria is a good way to prevent inflammation,” Matsuzawa said. They also indicated that other TKIs that do not affect the activity of mitochondrial SFKs may overcome the inflammatory-based side effects. As another approach, when effective inhibitors of the NLRP3 inflammasome are developed, administration of TKIs concomitantly with NLRP3 inhibitors could counteract the side effects. The team’s findings provide insight into both the biological and clinical significance of the inflammasome NLRP3 and SFKs.
Looking ahead, the team’s next step is to propose a new approach to avoid the inflammatory side effects of TKIs. They hope to lead the development of new TKIs that don’t cause inflammation.
The research team includes Yuto Sekiguchi, Saya Takano, Takuya Noguchi, Tomohiro Kaji, Ryoto Komatsu, Maoko Tan, Yusuke Hirata, and Atsushi Matsuzawa of the Health Chemistry Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan.
Sekiguchi, Y.; et al. (2023) The NLRP3 inflammatory fragment acts as a sensor to detect lack of activity in mitochondrial Src family kinases. Journal of Immunology. doi.org/10.4049/jimmunol.2200611.