Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. (https://pubmed.ncbi.nlm.nih.gov/38301010/)
These scientists wanted to understand why some patients with a type of blood cancer called B cell malignancies become resistant to certain drugs that are used to treat their condition. They focused on a protein called Bruton's tyrosine kinase (BTK), which is important for the growth and survival of cancer cells.
The scientists found that when patients were treated with drugs that inhibit BTK, some of the cancer cells developed mutations in the BTK protein. These mutations made the cancer cells resistant to the drugs, which means the drugs could no longer kill the cancer cells effectively.
The researchers discovered that these mutant BTK proteins had different activities compared to the normal BTK protein. Some of the mutant proteins were less effective at their normal job, which is to help send signals for the cancer cells to grow. However, these mutant proteins also gained new abilities to interact with other proteins in the cancer cells, which allowed them to continue sending signals for the cancer cells to grow.
To overcome this resistance, the scientists developed a new drug called NX-2127. This drug can bind to the mutant BTK proteins and mark them for destruction by a cellular recycling system called the proteasome. By doing this, NX-2127 effectively blocks the signals for cancer cell growth.
The scientists tested NX-2127 in patients with a specific type of blood cancer called chronic lymphocytic leukemia. They found that the drug could degrade more than 80% of the mutant BTK proteins in these patients. This means that the drug was able to get rid of a large portion of the proteins that were causing the cancer cells to grow.
This study shows that the mutant BTK proteins have a special function that helps them resist the drugs used to treat B cell malignancies. However, by using a new drug that can degrade these mutant proteins, the scientists were able to overcome this resistance and show that it could be a useful treatment for patients with this type of blood cancer.
Montoya S., Bourcier J., Noviski M., Lu H., Thompson MC., Chirino A., Jahn J., Sondhi AK., Gajewski S., Tan YSM., Yung S., Urban A., Wang E., Han C., Mi X., Kim WJ., Sievers Q., Auger P., Bousquet H., Brathaban N., Bravo B., Gessner M., Guiducci C., Iuliano JN., Kane T., Mukerji R., Reddy PJ., Powers J., Sanchez Garcia de Los Rios M., Ye J., Barrientos Risso C., Tsai D., Pardo G., Notti RQ., Pardo A., Affer M., Nawaratne V., Totiger TM., Pena-Velasquez C., Rhodes JM., Zelenetz AD., Alencar A., Roeker LE., Mehta S., Garippa R., Linley A., Soni RK., Skanland SS., Brown RJ., Mato AR., Hansen GM., Abdel-Wahab O., Taylor J. Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science. 2024 Feb 2;383(6682):eadi5798. doi: 10.1126/science.adi5798. Epub 2024 Feb 2.