Abstract IA006: Resistance to BTK degraders

Abstract

Pharmacological targeting of Bruton’s tyrosine kinase (BTK) has become one of the most successful therapeutic strategies introduced in recent years for patients with B-cell lymphoid malignancies. Depending on the country and indication, six BTK inhibitors — ibrutinib, zanubrutinib, acalabrutinib, orelabrutinib, tirabrutinib, and pirtobrutinib — have already been approved for the treatment of mature B-cell neoplasms, including chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, Waldenström’s macroglobulinemia, and primary central nervous system lymphoma. More recently, BTK degraders have emerged as a new generation of BTK-targeting agents. These bifunctional molecules induce BTK degradation by exploiting the endogenous ubiquitin–proteasome system. Also referred to as PROTACs (proteolysis-targeting chimeras), and in some cases as CDACs (chimeric degradation-activating compounds), BTK degraders are composed of three functional elements: a BTK-binding moiety, an E3 ubiquitin ligase–recruiting moiety, most commonly engaging CRBN or VHL, and a linker connecting the two. This strategy belongs to the broader field of proximity pharmacology, an increasingly important area in anticancer drug development. Several BTK degraders are currently undergoing clinical evaluation, including BGB-16673, bexobrutideg/NX-5948, zelebrudomide/NX-2127, AC676, ABBV-101, HSK29116, and HZ-Q1070, with BGB-16673 and bexobrutideg already being evaluated in phase 3 trials. The extensive clinical use of BTK inhibitors has revealed a wide spectrum of resistance mechanisms. In chronic lymphocytic leukemia, resistance is frequently associated with acquired mutations in BTK or PLCG2, whereas in other diseases, such as mantle cell lymphoma and marginal zone lymphoma, resistance more often involves signaling rewiring, pathway bypass, and broader cellular reprogramming. Importantly, individual BTK mutations may confer resistance to multiple inhibitors, while others appear to be preferentially selected by specific compounds, reflecting differences in drug–target binding and pharmacological properties. Clinical data on resistance to BTK degraders remain limited. Available evidence indicates that the BTK A428D mutation can confer resistance not only to BTK inhibitors, but also to several BTK degraders, including BGB-16673, zelebrudomide, ABBV-101, and bexobrutideg. In addition, mechanisms that bypass BTK-dependent signaling are expected to reduce the efficacy of BTK degraders, as they do for BTK inhibitors. Resistance may also arise through alterations affecting the degradation machinery itself, including genetic or epigenetic lesions involving components of the ubiquitin–proteasome system or the recruited E3 ligase complex. This presentation will review the emerging landscape of resistance to BTK degraders, integrating lessons learned from BTK inhibitors with the distinct vulnerabilities and potential escape mechanisms associated with targeted protein degradation.