Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL.
Identification of rational therapeutic targets is an important strategy to improve the cure rate of diffuse large B-cell lymphoma (DLBCL). We previously showed that inhibition of the phosphodiesterase 4B (PDE4B) unleashes cyclic-AMP (cAMP) inhibitory effects toward the PI3K/AKT pathway and induces apoptosis. These data raised important considerations as to which upstream regulators mediate cAMP inhibition of PI3K/AKT, and how identifying this signaling route could be translated into clinical initiatives. We found that in normal and malignant B cells, cAMP potently inhibit the phosphorylation and activity of the tyrosine kinase SYK. Using genetic models of gain- and loss-of-function, we demonstrated the essential role for PDE4B in controlling these effects in DLBCL. Furthermore, we used a constitutively active SYK mutant to confirm its central role in transducing cAMP effects to PI3K/AKT. Importantly, given SYK credentials as a therapeutic target in B-cell tumors, we explored the role of PDE4B in these responses. In multiple DLBCL models, we found that genetically, hence specifically, inhibiting PDE4B expression significantly improved the efficacy of SYK inhibitors. Our data defined a hitherto unknown role for cAMP in negatively regulating SYK and indicate that combined inhibition of PDE4B and SYK should be actively pursued.
Kim
Sang-Woo
SW
Division of Hematology and Medical Oncology, Department of Medicine, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Rai
Deepak
D
McKeller
Morgan R
MR
Aguiar
Ricardo C T
RC
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D000072377:Syk Kinase
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D058988:Phosphodiesterase 4 Inhibitors; D034741:RNA, Small Interfering; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human