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Targeting BTK in B Cell Malignancies: From Mode of Action to Resistance Mechanisms.
Mouhssine, Samir; Maher, Nawar; Matti, Bassam Francis; Alwan, Alaa Fadhil; Gaidano, Gianluca.
Afiliación
  • Mouhssine S; Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carità, 28100 Novara, Italy.
  • Maher N; Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carità, 28100 Novara, Italy.
  • Matti BF; Department of Hematology and Bone Marrow Transplant, Hematology and Bone Marrow Transplant Center, Medical City, Baghdad 00964, Iraq.
  • Alwan AF; Department of Hematology and Bone Marrow Transplant, Hematology and Bone Marrow Transplant Center, Medical City, Baghdad 00964, Iraq.
  • Gaidano G; Department of Clinical Hematology, The National Center of Hematology, Mustansiriyah University, Baghdad 10015, Iraq.
Int J Mol Sci ; 25(6)2024 Mar 12.
Article en En | MEDLINE | ID: mdl-38542207
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Linfocítica Crónica de Células B / Linfoma de Células B Grandes Difuso Límite: Adult / Humans Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Linfocítica Crónica de Células B / Linfoma de Células B Grandes Difuso Límite: Adult / Humans Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Suiza