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ESH CLL 2026 | BTK degraders: mechanism and overcoming resistance in CLL
Justin Taylor, MD, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, discusses the mechanism of action of BTK degraders in chronic lymphocytic leukemia (CLL) and how they differ from current BTK inhibitors. He highlights their ability to target both kinase and non-kinase functions of BTK and their potential to overcome resistance seen with covalent and non-covalent inhibitors. This interview took place at the ESH CLL 2026 congress in Stockholm, Sweden.
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Transcript
So BTK degraders are exciting, and as opposed to current BTK inhibitors, these actually degrade the whole protein. So one advantage of that is that it blocks the kinase effects of BTK, but also the non-kinase or scaffold effects. Another advantage of these is after BTK is degraded, the degrader can be recycled and used again. So the dosing is actually different than covalent BTK inhibitors, which once BTK gets recycled, the covalent inhibitors go with them and you have to dose again...
So BTK degraders are exciting, and as opposed to current BTK inhibitors, these actually degrade the whole protein. So one advantage of that is that it blocks the kinase effects of BTK, but also the non-kinase or scaffold effects. Another advantage of these is after BTK is degraded, the degrader can be recycled and used again. So the dosing is actually different than covalent BTK inhibitors, which once BTK gets recycled, the covalent inhibitors go with them and you have to dose again. The last one is potential to overcome resistance mutations to the covalent and non-covalent.
Resistance to covalent and non-covalent BTK inhibitors can happen through different ways, but of the types of mutations that are in BTK itself, the degraders have the possibility to overcome those because that binding to BTK is not abrogated by those mutations. There are other ways to get BTK inhibitor resistance that we don’t know for sure if the degraders will be able to address those. But at least in the clinical trials, the patients previously treated with covalent or non-covalent BTK inhibitors do seem to respond to the degraders, so suggesting that they will overcome most of the resistance to those types of therapies.
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