Molecular and Structural Basis of Pan-Resistance to BTK Degraders and Inhibitors
Year: 2026
Type: article
Abstract: Early-phase clinical trials of Bruton’s tyrosine kinase (BTK) degraders have demonstrated efficacy in patients with BTK inhibitor–resistant chronic lymphocytic leukemia (CLL). How clinical resistance to BTK degraders arises is unknown. In this study, we sequenced serial CLL samples from patients enrolled in phase I trials of zelebrudomide and bexobrutideg and observed recurrent expansion of preexisting BTKA428D mutations at relapse. Unlike previously studied BTK inhibitor resistance mutations, BTKA428D conferred pan-resistance to BTK inhibitors and degraders. In the absence of BTK-directed therapies, however, cells bearing BTKA428D exhibited a competitive disadvantage. A crystal structure of BTKA428D revealed that the mutant aspartate clashes with the adenine ring of adenosine triphosphate and the adenine-mimetic moiety of BTK inhibitors and degraders. Combining BTK degraders with venetoclax mitigated the expansion of BTKA428D. These results provide the molecular basis for clinical resistance to BTK degraders and will inform the development of next-generation BTK degrader therapies. Significance: BTK degraders are a promising new therapy for CLL. We demonstrate that BTKA428D is a recurrent BTK degrader resistance mutation in patients that confers pan-resistance to BTK inhibitors and degraders due to steric clash with their shared, adenine-mimetic moiety. Understanding this mutation can guide the development of next-generation BTK degraders.
Source: Cancer Discovery
Authors: Quinlan Sievers, Hao Lu, Allison Cool, Stefan Gajewski, Tim Kong, Mark A. Noviski, Sarah Whelan, Yuhan Wang, Lizbeth Mendoza Navarrete, Xiaoli Mi, Emel Ficici, Ratul Mukerji, James N. Iuliano, Jordan Ye, Mateo Sanchez Garcia De Los Rios, Hugo Bousquet, May Tan, Nivetha Brathaban, Nell Narasappa, Ya-Wen Lu, Jennifer Elechko, Maxim I. Maron, Christopher B. Phelps, Jahan Rahman, Ryan Q. Notti, Samantha Sekeres, Erica N. Lamkin, Eduardo Bravo, Alvaro Alencar, Mark D. Ewalt, Prioty Islam, Anthony R. Mato, Lindsey Roeker, Shruti Bhatt, Justin Taylor, Meghan C. Thompson, Gwenn M. Hansen, Omar Abdel-Wahab
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: American Cancer Society, Damon Runyon Cancer Research Foundation, American Society of Hematology, Leukemia Research Foundation, Florida Department of Health, Memorial Sloan-Kettering Cancer Center, Edward P. Evans Foundation, Gerstner Family Foundation, Break Through Cancer, Cycle for Survival, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences
Awards: G1158233253, G4039569666, G5790647484, G752229251, G887357334, G9000846572, G9000846835, Cancer Center Support Grant, Understanding mechanisms of BTK inhibitor and degrader resistance in patients with chronic lymphocytic leukemia, The Memorial Sloan Kettering Cancer Center SPORE in Leukemia, The role of XPO1 in nuclear export of RNA
OpenAlex ID: W7170032813