Mechanisms of resistance to BTK inhibitors in B cell malignancies and emerging targeted strategies

Bruton tyrosine kinase inhibitors (BTKis) have markedly improved the treatment landscape for B cell malignancies, including chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B cell lymphoma, and Waldenström's macroglobulinemia, since the introduction of the first-in-class BTKi, ibrutinib, a decade ago. Despite their clinical success, the emergence of resistance to BTKis poses a significant therapeutic challenge. The mechanisms of resistance are multifactorial and include genetic mutations, activation of alternative oncogenic signaling pathways, dysregulated protein expression, alterations in the tumor microenvironment, and metabolic reprogramming. To address these challenges, several therapeutic strategies are under active investigation, such as next-generation noncovalent BTKis, BTK-targeting proteolysis approaches (e.g., PROTACs), and combination therapies (e.g., with bispecific antibodies or chimeric antigen receptor T [CAR T] cells) designed to bypass or overcome resistance pathways. This review provides a comprehensive overview of the mechanisms driving BTKi resistance and discusses current preclinical and clinical strategies aimed at improving therapeutic outcomes in B cell malignancies.