RESUMO
To elucidate their mechanism of action, inhibitors of Bruton tyrosine kinase (BTK) and resistant BTK mutants were employed to dissect target-dependent cellular functions. BTK-C481S and -T474I, expressed in Ramos and NALM-6 cells, maintained BTK auto-phosphorylation under treatment with ibrutinib or dasatinib, respectively, which showed only modest cytotoxicity. Retained activity of BTK-T474 partially rescued cell migration from inhibition by dasatinib. Importantly, resistant BTK mutants reconstituted B cell receptor-triggered chemokine secretion in the presence of corresponding inhibitors, demonstrating that BTK activity is connected with cell-intrinsic functions of malignant B cells with importance for their dialogue with the micro-environment.
Assuntos
Linfócitos B/enzimologia , Leucemia de Células B/genética , Linfoma de Células B/genética , Proteínas Tirosina Quinases/genética , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Antineoplásicos , Quimiocinas/metabolismo , Quimiotaxia/efeitos dos fármacos , Dasatinibe/administração & dosagem , Dasatinibe/farmacologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Leucemia de Células B/enzimologia , Leucemia de Células B/patologia , Linfoma de Células B/enzimologia , Linfoma de Células B/patologia , Mutação , Fosforilação/efeitos dos fármacos , Piperidinas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Células Tumorais CultivadasRESUMO
Advanced Therapy Medicinal Products (ATMPs) comprising cell, gene, and tissue-engineered therapies have demonstrated enormous therapeutic benefits. However, their development is complex to be managed efficiently within currently existing regulatory frameworks. Legislation and regulation requirements for ATMPs must strike a balance between the patient safety while promoting innovations to optimize exploitation of these novel therapeutics. This paradox highlights the importance of on-going dynamic dialogue between all stakeholders and regulatory science to facilitate the development of pragmatic ATMP regulatory guidelines.