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Published on: October 4, 2018
Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL
Sang-Woo Kim1, Deepak Rai, Morgan R McKeller
1Division 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.
Abstract:
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.
Insights
In diffuse large B-cell lymphoma (DLBCL), cyclic-AMP (cAMP) inhibits the PI3K/AKT pathway via the tyrosine kinase SYK. Inhibiting phosphodiesterase 4B (PDE4B) enhances this effect, improving SYK inhibitor efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Diffuse large B-cell lymphoma (DLBCL) requires novel therapeutic targets for improved cure rates.
- Phosphodiesterase 4B (PDE4B) inhibition increases cyclic-AMP (cAMP), impacting the PI3K/AKT pathway and inducing apoptosis.
- Understanding upstream regulators of cAMP-mediated PI3K/AKT inhibition is crucial for clinical translation.
Purpose of the Study:
- To identify upstream regulators mediating cAMP's inhibition of the PI3K/AKT pathway in DLBCL.
- To investigate the role of the tyrosine kinase SYK in this signaling cascade.
- To explore the therapeutic potential of combining PDE4B and SYK inhibition in DLBCL models.
Main Methods:
- Investigated cAMP's effect on SYK phosphorylation and activity in normal and malignant B cells.
- Utilized genetic gain- and loss-of-function models to assess PDE4B's role in DLBCL.
- Employed a constitutively active SYK mutant to confirm its role in cAMP signaling.
- Evaluated the efficacy of combined PDE4B and SYK inhibition in DLBCL models.
Main Results:
- Cyclic-AMP (cAMP) potently inhibits SYK phosphorylation and activity in B cells.
- PDE4B is essential for mediating cAMP's inhibitory effects on SYK in DLBCL.
- Genetic inhibition of PDE4B significantly enhances the efficacy of SYK inhibitors in DLBCL models.
Conclusions:
- A novel signaling pathway is defined where cAMP negatively regulates SYK.
- Combined inhibition of PDE4B and SYK represents a promising therapeutic strategy for DLBCL.
- Targeting PDE4B offers a means to potentiate SYK-targeted therapies in B-cell malignancies.
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