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- Title
Targeting BTK in B Cell Malignancies: From Mode of Action to Resistance Mechanisms.
- Authors
Mouhssine, Samir; Maher, Nawar; Matti, Bassam Francis; Alwan, Alaa Fadhil; Gaidano, Gianluca
- Abstract
The B cell receptor (BCR) signaling pathway plays a crucial role in B cell development and contributes to the pathogenesis of B cell neoplasms. In B cell malignancies, the BCR is constitutively active through both ligand-dependent and ligand-independent mechanisms, resulting in continuous Bruton tyrosine kinase (BTK) signaling activation, which provides a survival and proliferation advantage to the neoplastic clone. Among B cell malignancies, those in which the most significant results were obtained by treatment with BTK inhibitors (BTKi) include chronic lymphocytic leukemia, mantle cell lymphoma, lymphoplasmacytic lymphoma, and diffuse large B cell lymphoma. Covalent BTKi (namely ibrutinib, acalabrutinib, and zanubrutinib) functions by irreversibly blocking BTK through covalent binding to the cysteine residue 481 (Cys-481) in the ATP-binding domain. Despite the high efficacy and safety of BTKi treatment, a significant fraction of patients affected by B cell malignancies who are treated with these drugs experience disease relapse. Several mechanisms of resistance to covalent BTKi, including Cys-481 mutations of BTK, have been investigated in B cell malignancies. Non-covalent BTKi, such as pirtobrutinib, have been developed and proven effective in patients carrying both Cys-481-mutated and unmutated BTK. Moreover, targeting BTK with proteolysis-targeting chimeras (PROTACs) represents a promising strategy to overcome resistance to BTKi in B cell neoplasms.
- Subjects
B cells; B cell lymphoma; BRUTON tyrosine kinase; MANTLE cell lymphoma; B cell receptors; WALDENSTROM'S macroglobulinemia
- Publication
International Journal of Molecular Sciences, 2024, Vol 25, Issue 6, p3234
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms25063234