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The Evolving Role of Bruton's Tyrosine Kinase Inhibitors in B Cell Lymphomas.
Mehra, Shefali; Nicholls, Miah; Taylor, Justin.
Afiliação
  • Mehra S; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  • Nicholls M; College of Arts and Sciences, University of Miami, Coral Gables, FL 33146, USA.
  • Taylor J; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Int J Mol Sci ; 25(14)2024 Jul 09.
Article em En | MEDLINE | ID: mdl-39062757
ABSTRACT
Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase crucial for B cell development and function, acts downstream of the B cell receptor (BCR) in the BCR pathway. Other kinases involved downstream of the BCR besides BTK such as Syk, Lyn, PI3K, and Mitogen-activated protein (MAP) kinases also play roles in relaying signals from the BCR to provide pro-survival, activation, and proliferation cues. BTK signaling is implicated in various B-cell lymphomas such as mantle cell lymphoma, Waldenström Macroglobulinemia, follicular lymphoma, and diffuse large B cell lymphoma, leading to the development of transformative treatments like ibrutinib, the first-in-class covalent BTK inhibitor, and pirtobrutinib, the first-in-class noncovalent BTK inhibitor. However, kinase-deficient mutations C481F, C481Y, C481R, and L528W in the BTK gene confer resistance to both covalent and non-covalent BTK inhibitors, facilitating B cell survival and lymphomagenesis despite kinase inactivation. Further studies have revealed BTK's non-catalytic scaffolding function, mediating the assembly and activation of proteins including Toll-like receptor 9 (TLR9), vascular cell adhesion protein 1 (VCAM-1), hematopoietic cell kinase (HCK), and integrin-linked kinase (ILK). This non-enzymatic role promotes cell survival and proliferation independently of kinase activity. Understanding BTK's dual roles unveils opportunities for therapeutics targeting its scaffolding function, promising advancements in disrupting lymphomagenesis and refining B cell lymphoma treatments.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfoma de Células B / Inibidores de Proteínas Quinases / Tirosina Quinase da Agamaglobulinemia Limite: Animals / Humans Idioma: En Revista: Int J Mol Sci Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfoma de Células B / Inibidores de Proteínas Quinases / Tirosina Quinase da Agamaglobulinemia Limite: Animals / Humans Idioma: En Revista: Int J Mol Sci Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos