Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL

摘要: Identification of rational therapeutic targets is an important strategy to improve the cure rate diffuse large B-cell lymphoma (DLBCL). We previously showed that inhibition phosphodiesterase 4B (PDE4B) unleashes cyclic-AMP (cAMP) inhibitory effects toward PI3K/AKT pathway and induces apoptosis. These data raised considerations as which upstream regulators mediate cAMP PI3K/AKT, how identifying this signaling route could be translated into clinical initiatives. found in normal malignant B cells, potently inhibit phosphorylation activity tyrosine kinase SYK. Using genetic models gain- loss-of-function, we demonstrated essential role for PDE4B controlling these DLBCL. Furthermore, used a constitutively active SYK mutant confirm its central transducing PI3K/AKT. Importantly, given credentials target tumors, explored responses. In multiple DLBCL models, genetically, hence specifically, inhibiting expression significantly improved efficacy inhibitors. Our defined hitherto unknown negatively regulating indicate combined should actively pursued.