Abstract
Bruton tyrosine kinase (BTK), an essential component of the B-cell receptor (BCR) signaling pathway, is a validated target in chronic lymphocytic leukemia. Ibrutinib, acalabrutinib, and zanubrutinib are covalent BTK inhibitors (cBTKi) that bind to residue C481, leading to sustained target inhibition. A significant proportion of patients develop resistance to continuous cBTKi therapy, predominantly via mutations in BTK and its immediate downstream effector, PLCG2. The noncovalent BTKi pirtobrutinib does not require binding to C481 and can restore BTK inhibition after progression on a cBTKi. However, non-C481 BTK mutations conferring resistance to pirtobrutinib have been identified. Furthermore, the scaffolding function of BTK, activation of bypass signaling pathways, and the tumor microenvironment may contribute to BTKi resistance. Targeting BTK for degradation is an emerging strategy that appears effective against multiple BTK mutations, and inhibitors of downstream BCR signaling proteins are under development. This review addresses BTKi resistance mechanisms and therapeutic approaches after cBTKi failure.