Inhibition of the STAT3 target SGK1 sensitizes diffuse large B cell lymphoma cells to AKT inhibitors.
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ABSTRACT:
SUBMITTER: Lu L
PROVIDER: S-EPMC6441016 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
Publications
Inhibition of the STAT3 target SGK1 sensitizes diffuse large B cell lymphoma cells to AKT inhibitors.
Lu Li L Zhu Fen F Li Yangguang Y Kimpara Shuichi S Hoang Nguyet Minh NM Pourdashti Sheida S Rui Lixin L
Blood cancer journal 20190329 4
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| S-EPMC5286945 | biostudies-literature
Project description:Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, is characterized by an aggressive clinical course. In approximately one-third of DLBCL patients, first-line multi-agent immunochemotherapy fails to produce a durable response. Molecular heterogeneity and apoptosis resistance pose major therapeutic challenges in DLBCL treatment. To circumvent apoptosis resistance, the induction of ferroptosis might represent a promising strategy for lymphoma therapy. Here, a compound library targeting epigenetic modulators was screened to identify ferroptosis-sensitizing drugs. Strikingly, bromodomain and extra-terminal domain (BET) inhibitors sensitized cells of the germinal center B cell-like (GCB) subtype of DLBCL to ferroptosis induction and the combination of BET inhibitors with ferroptosis inducers, such as dimethyl fumarate (DMF) or RSL3, synergized in the killing of DLBCL cells in vitro and in vivo. On the molecular level, the BET protein BRD4 was found to be an essential regulator of ferroptosis suppressor protein 1 (FSP1) expression and to thus protect GCB DLBCL cells from ferroptosis. Collectively, we identified and characterized BRD4 as an important player in ferroptosis suppression in GCB DLBCL and provide a rationale for the combination of BET inhibitors with ferroptosis-inducing agents as a novel therapeutic approach for DLBCL treatment.
2023-08-01 | GSE231871 | GEO
Project description:Persistent STAT3 signaling contributes to malignant progression in many diverse types of human cancer. STAT3 is constitutively active in activated B-cell (ABC)-like diffuse large B-cell lymphomas (DLBCL), a class of nongerminal center derived DLBCL cells for which existing therapy is weakly effective. In this report, we provide a preclinical proof of concept that STAT3 is an effective molecular target for ABC-like DLBCL therapy. Direct inhibition of STAT3 with short hairpin RNA suppressed the growth of human ABC-like DLBCL in mouse models in a manner associated with apoptosis, repression of STAT3 target genes, and inhibition of a tumor-promoting microenvironment. Together, these results suggest that STAT3 is essential to maintain the pathophysiology of ABC-like DLBCL and therefore that STAT3 inhibition may offer a promising approach in its therapy.
| S-EPMC3085657 | biostudies-literature
Project description:Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands.
| S-EPMC5004937 | biostudies-literature
Project description:The mTOR pathway is constitutively activated in diffuse large B-cell lymphoma (DLBCL). mTOR inhibitors have activity in DLBCL, although response rates remain low. We evaluated DLBCL cell lines with differential resistance to the mTOR inhibitor rapamycin: (i) to identify gene expression profile(s) (GEP) associated with resistance to rapamycin, (ii) to understand mechanisms of rapamycin resistance, and (iii) to identify compounds likely to synergize with mTOR inhibitor.We sought to identify a GEP of mTOR inhibitor resistance by stratification of eight DLBCL cell lines with respect to response to rapamycin. Then, using pathway analysis and connectivity mapping, we sought targets likely accounting for this resistance and compounds likely to overcome it. We then evaluated two compounds thus identified for their potential to synergize with rapamycin in DLBCL and confirmed mechanisms of activity with standard immunoassays.We identified a GEP capable of reliably distinguishing rapamycin-resistant from rapamycin-sensitive DLBCL cell lines. Pathway analysis identified Akt as central to the differentially expressed gene network. Connectivity mapping identified compounds targeting Akt as having a high likelihood of reversing the GEP associated with mTOR inhibitor resistance. Nelfinavir and MK-2206, chosen for their Akt-inhibitory properties, yielded synergistic inhibition of cell viability in combination with rapamycin in DLBCL cell lines, and potently inhibited phosphorylation of Akt and downstream targets of activated mTOR.GEP identifies DLBCL subsets resistant to mTOR inhibitor therapy. Combined targeting of mTOR and Akt suppresses activation of key components of the Akt/mTOR pathway and results in synergistic cytotoxicity. These findings are readily adaptable to clinical trials.
| S-EPMC3889476 | biostudies-literature
Project description:Up to one-third of diffuse large B cell lymphoma (DLBCL) patients eventually develop resistance to R-CHOP regimen, while the remaining therapeutic options are limited. Thus, understanding the underlying mechanisms and developing therapeutic approaches are urgently needed. Methods: We generated two germinal center B cell-like (GCB) and activated B cell-like (ABC) subtype R-CHO resistant DLBCL cell lines, of which the tumor-initiating capacity was evaluated by serial-transplantation and stemness-associated features including CD34 and CD133 expression, side population and ALDH1 activity were detected by flow cytometry or immunoblotting. Expression profiles of these resistant cells were characterized by RNA sequencing. The susceptibility of resistant cells to different treatments was evaluated by in vitro CytoTox-glo assay and in tumor-bearing mice. The expression levels of SOX2, phos-AKT, CDK6 and FGFR1/2 were detected in 12 R-CHOP-resistant DLBCL clinical specimens by IHC. Results: The stem-like CSC proportion significantly increased in both resistant DLBCL subtypes. SOX2 expression level remarkably elevated in both resistant cell lines due to its phosphorylation by activated PI3K/AKT signaling, thus preventing ubiquitin-mediated degradation. Further, multiple factors, including BCR, integrins, chemokines and FGFR1/2 signaling, regulated PI3K/AKT activation. CDK6 in GCB subtype and FGFR1/2 in ABC subtype were SOX2 targets, whose inhibition potently re-sensitized resistant cells to R-CHOP treatment. More importantly, addition of PI3K inhibitor to R-CHOP completely suppressed the tumor growth of R-CHO-resistant DLBCL cells, most likely by converting CSCs to chemo-sensitive differentiated cells. Conclusions: The PI3K/AKT/SOX2 axis plays a critical role in R-CHOP resistance development and the pro-differentiation therapy against CSCs proposed in this study warrants further study in clinical trials for the treatment of resistant DLBCL.
| S-EPMC7053184 | biostudies-literature
Project description:Agents that target components of the PI3K/AKT/mTOR pathway are under investigation for the treatment of diffuse large B cell lymphoma (DLBCL). Given the highly heterogeneous nature of DLBCL, it is not clear whether all subtypes of DLBCL will be susceptible to PI3K pathway inhibition, or which kinase within this pathway is the most favorable target. Pharmacological profiling of a panel of DLBCL cell lines revealed a subset of DLBCL that was resistant to AKT inhibition. Strikingly, sensitivity to AKT inhibitors correlated with the ability of these inhibitors to block phosphorylation of S6K1 and ribosomal protein S6. Cell lines resistant to AKT inhibition activated S6K1 independent of AKT either through upregulation of PIM2 or through activation by B cell receptor (BCR) signaling components. Finally, combined inhibition of AKT and BTK, PIM2, or S6K1 proved to be an effective strategy to overcome resistance to AKT inhibition in DLBCL.
| S-EPMC4891033 | biostudies-literature
Project description:Treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has greatly improved clinical outcomes in patients with diffuse large B-cell lymphoma (DLBCL) compared with CHOP. The mechanism of rituximab-induced cell death is poorly understood. We found that rituximab does not enhance the directly killing efficacy of CHOP, as tested on a panel of DLBCL cell lines. Rituximab induced a rapid release of HMGB1 (High mobility group protein B 1). This release is independent of cell death but significantly correlated with an inhibition on STAT3 activity. In the resting state, HMGB1 co-localizes and interacts with STAT3 in the nucleus of DLBCL cells. Treatment with rituximab breaks this binding and triggers HMGB1 release. Treatment with R-CHOP but not CHOP significantly increased plasma HMGB1 and decreased IL-10 concentrations in DLBCL patients compared with controls. The conditioned medium from rituximab-treated DLBCL cells is able to trigger dendritic cell maturation, phagocytosis, and IFN-γ secretion by cytotoxic T cells. In conclusion, our results demonstrate that rituximab induces an inhibition on STAT3 activity, leading to increased HMGB1 release and decreased IL-10 secretion, which elicits immune responses, suggesting that indirect effects on the immune system rather than direct killing contribute to elimination of DLBCL.
| S-EPMC4695028 | biostudies-literature
Project description:Persistent STAT3 activation has been found in activated B-cell like diffuse large B cell tumors (DLBCL). To investigate whether genetic mutations play a role in aberrant STAT3 signaling in DLBCL, we bi-directionally sequenced all 24 exons of the STAT3 gene in DLBCL tumors (n = 40). We identified 2 novel point mutations in 2 separate (2/40; 5%) patients at exon 7 and 24. Point mutation 2552G>A was a silent mutation in the stop codon. Another heterozygous mutation 857T>A encoded a methionine substitution by lysine at codon 206 (M206K) in the coiled-coil domain of STAT3. We performed site directed mutagenesis to mutate wild type (WT) STAT3α and STAT3β at codon 206 and constructed stable cell lines by lentiviral transfection of STAT3α(WT), STAT3α(M206K), STAT3β(WT) and STAT3β(M206K) plasmids. The mutation was found to increase STAT3 phosphorylation in STAT3α mutant cell lines with no effect on the STAT3β mutant cell line. Transcriptional activation was also increased in the STAT3α mutant cells compared with STAT3α WT cells as detected by a luciferase reporter assay. Moreover, STAT3α(M206K) mutant cells were resistant to JAK2 pathway inhibition compared to STAT3α WT cells. These results indicate that missense mutations in STAT3 increase signaling through the JAK/STAT pathway. JAK2 inhibitors may be useful in the patient with this STAT3 mutation as well as those with pathway activation by other mechanisms.
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