Exploring novel therapeutic targets of Diffuse large B cell lymphoma(DLBCL)to overcome its resistance to Bruton's Tyrosine Kinase(BTK)inhibitors is a key topic.Lipid metabolism,crucial in the resistance landscape ...Exploring novel therapeutic targets of Diffuse large B cell lymphoma(DLBCL)to overcome its resistance to Bruton's Tyrosine Kinase(BTK)inhibitors is a key topic.Lipid metabolism,crucial in the resistance landscape of various cancers,may unlock new aspects of BTK inhibitor resistance in DLBCL.Despite the known importance of lipid metabolism in oncological resistance patterns,its intricate role in DLBCL and its resistance to BTK inhibitor therapies remains largely uncharted.This review will explore the complex relationship between lipid metabolism and BTK inhibitor resistance,giving new insights for improving the effectiveness of BTK inhibitors and developing innovative combination treatment methods for DLBCL.This review holds the potential for guiding future research directions,optimizing existing therapeutic processes,and inspiring the development of innovative combinatorial therapeutic strategies that improve outcomes in patients with DLBCL.展开更多
Objective:B-cell antigen receptor(BCR)signaling is required to maintain the physiological functions of normal B cells and plays an important pathogenic role in B-cell malignancies.Bruton tyrosine kinase(BTK),a critica...Objective:B-cell antigen receptor(BCR)signaling is required to maintain the physiological functions of normal B cells and plays an important pathogenic role in B-cell malignancies.Bruton tyrosine kinase(BTK),a critical mediator of BCR signaling,is an attractive target for the treatment of B-cell malignancies.This study aimed to identify a highly potent and selective BTK inhibitor.Methods:Homogeneous time-resolved fluorescence assays were used to screen BTK inhibitors.Typhoon fluorescence imaging and Western blot analysis were used to confirm the effects of SY-1530 on the BCR signaling pathway.Additionally,the anti-tumor activities of SY-1530 were evaluated in TMD8 xenografts and spontaneous canine B-cell lymphoma.Results:We found a novel irreversible and non-competitive inhibitor of BTK,SY-1530,which provided dose-dependent and timedependent inhibition.SY-1530 selectively bound to BTK rather than inducible T-cell kinase;consequently,it did not significantly affect T-cell receptor signaling and caused limited off-target effects.SY-1530 blocked the BCR signaling pathway through downregulation of BTK activity,thus leading to impaired phosphorylation of BTK and its downstream kinases.Moreover,SY-1530 induced apoptosis in a caspase-dependent manner and efficaciously inhibited tumor growth in mouse xenograft models of B-cell malignancy(P<0.001).SY-1530 also induced positive clinical responses in spontaneous canine B-cell lymphoma.Conclusions:SY-1530 is an irreversible and selective BTK inhibitor that shows inhibitory effects on B-cell malignancies by blocking the BCR signaling pathway.Therefore,it may be a promising therapeutic approach for the treatment of B-cell malignancies.展开更多
基金supported by the Academic Excellence Foundation of BUAA for PhD Students.
文摘Exploring novel therapeutic targets of Diffuse large B cell lymphoma(DLBCL)to overcome its resistance to Bruton's Tyrosine Kinase(BTK)inhibitors is a key topic.Lipid metabolism,crucial in the resistance landscape of various cancers,may unlock new aspects of BTK inhibitor resistance in DLBCL.Despite the known importance of lipid metabolism in oncological resistance patterns,its intricate role in DLBCL and its resistance to BTK inhibitor therapies remains largely uncharted.This review will explore the complex relationship between lipid metabolism and BTK inhibitor resistance,giving new insights for improving the effectiveness of BTK inhibitors and developing innovative combination treatment methods for DLBCL.This review holds the potential for guiding future research directions,optimizing existing therapeutic processes,and inspiring the development of innovative combinatorial therapeutic strategies that improve outcomes in patients with DLBCL.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.81622037,81672762,and 81372185)and the Beijing Natural Science Foundation(Grant No.5194023).
文摘Objective:B-cell antigen receptor(BCR)signaling is required to maintain the physiological functions of normal B cells and plays an important pathogenic role in B-cell malignancies.Bruton tyrosine kinase(BTK),a critical mediator of BCR signaling,is an attractive target for the treatment of B-cell malignancies.This study aimed to identify a highly potent and selective BTK inhibitor.Methods:Homogeneous time-resolved fluorescence assays were used to screen BTK inhibitors.Typhoon fluorescence imaging and Western blot analysis were used to confirm the effects of SY-1530 on the BCR signaling pathway.Additionally,the anti-tumor activities of SY-1530 were evaluated in TMD8 xenografts and spontaneous canine B-cell lymphoma.Results:We found a novel irreversible and non-competitive inhibitor of BTK,SY-1530,which provided dose-dependent and timedependent inhibition.SY-1530 selectively bound to BTK rather than inducible T-cell kinase;consequently,it did not significantly affect T-cell receptor signaling and caused limited off-target effects.SY-1530 blocked the BCR signaling pathway through downregulation of BTK activity,thus leading to impaired phosphorylation of BTK and its downstream kinases.Moreover,SY-1530 induced apoptosis in a caspase-dependent manner and efficaciously inhibited tumor growth in mouse xenograft models of B-cell malignancy(P<0.001).SY-1530 also induced positive clinical responses in spontaneous canine B-cell lymphoma.Conclusions:SY-1530 is an irreversible and selective BTK inhibitor that shows inhibitory effects on B-cell malignancies by blocking the BCR signaling pathway.Therefore,it may be a promising therapeutic approach for the treatment of B-cell malignancies.
