Inhibition of the STAT3 target SGK1 sensitizes diffuse large B cell lymphoma cells to AKT inhibitors

STAT3 Activation and Oncogenesis in Lymphoma

“…We also performed genome-wide analysis in both ABC DLBCL and normal activated B-cells and identified 1014 STAT3 targets that are specific for ABC DLBCL, including the immune checkpoint molecule PD-L1, the transcriptional activator MEF2B, the hematopoietic cell kinase (HCK), the Epstein-Barr virus-induced genes 3 (EBI3), and genes involved in regulating cellular metabolism (e.g., SCARB1) [77]. PD-L1 is a well-studied immune checkpoint molecule that binds to the inhibitory PD-1 receptor on T-cells and suppresses T-cell activation [82].…”

“…To investigate the molecular mechanisms underlying STAT3 oncogenesis in ABC DLBCL, we recently identified~2000 STAT3 target genes in ABC DLBCL by genomic analysis [35]. These include NF-κB pathway genes (e.g., NFKB2, NFKBIA, NFKBIZ, CXCL13, and TRAF1), JAK/STAT pathway genes (e.g., IL-10, SOCS3, and STAT3), antiapoptotic pathway genes (e.g., BCL2, MCL1, BCL2L11, and CASP8), and PI3K/AKT/mTORC1 pathway genes (e.g., AKT2, SCL7A11, and ACSL3) ( Figure 2) [35,77]. In addition, STAT3 functions as a transcriptional suppressor and inhibits transcription of genes in the type I interferon signaling pathway, including IRF7, IRF9, STAT1, and STAT2 [35,77].…”

“…These include NF-κB pathway genes (e.g., NFKB2, NFKBIA, NFKBIZ, CXCL13, and TRAF1), JAK/STAT pathway genes (e.g., IL-10, SOCS3, and STAT3), antiapoptotic pathway genes (e.g., BCL2, MCL1, BCL2L11, and CASP8), and PI3K/AKT/mTORC1 pathway genes (e.g., AKT2, SCL7A11, and ACSL3) ( Figure 2) [35,77]. In addition, STAT3 functions as a transcriptional suppressor and inhibits transcription of genes in the type I interferon signaling pathway, including IRF7, IRF9, STAT1, and STAT2 [35,77]. Anti-type I interferon properties of STAT3 have been characterized as an antiviral defense mechanism [78][79][80].…”

“…Our recent studies suggest several potential combination therapeutic strategies in DLBCL [35,70,77]. In ABC DLBCL, the crosstalk between JAK1 and NF-κB signaling promotes cancer cell survival [70].…”

“…Co-treatment of Ruxolitinib and the type I interferon inducer lenalidomide inhibits growth of ABC DLBCL cells in vitro and in vivo [35]. Inhibition of SGK1, a target gene of STAT3, by its inhibitor synergizes with AKT inhibitors in the killing of ABC DLBCL cells [77].…”