Degrader outmaneuvers cancer target BTK

Degrading Bruton’s tyrosine kinase (BTK)—a popular cancer target—rather than just blocking the enzyme’s action, eliminates BTK mutants that have developed resistance to existing drugs. The finding suggests that protein degradation can treat people with certain drug-resistant cancers and could guide researchers to other drug targets that act in concert with BTK.

BTK is involved in the signaling related to B-cell development. Several drugs that inhibit BTK, such as ibrutinib, have been successful at treating chronic lymphocytic leukemia and other cancers. But over time, BTK can mutate so that these drugs no longer have any effect on the enzyme—sometimes the mutation kills the enzyme’s kinase activity.

In a new study, researchers found that even when these BTK mutants are enzymatically dead, they still participate in the signaling process that causes B-cell growth and cancer proliferation. “This is surprising, because if you delete BTK altogether, the B cells will die,” says Omar Abdel-Wahab at Memorial Sloan Kettering Cancer Center. He led the research along with Justin Taylor at the University of Miami’s Miller School of Medicine and Gwenn Hansen at Nurix Therapeutics. The findings suggest that inert BTK helps the signaling function of other enzymes that could also be drug targets (Science 2024, DOI: 10.1126/science.adi5798).

The researchers used the degrader NX-2127, which tags BTK to be broken down by the cell’s trash removal system. The drug candidate eliminated over 80% of BTK in people with chronic lymphocytic leukemia in an ongoing Phase 1 clinical trial.