Submitted February 17, 2009
Accepted April 10, 2009
Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL
Sang-Woo Kim, Deepak Rai, Morgan R McKeller, and Ricardo C. T. Aguiar*
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, United States
* Corresponding author; email: aguiarr{at}uthscsa.edu.
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 towards the PI3K/AKT pathway, and induces apoptosis in DLBCL. 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
