CX-4945, a Selective Inhibitor of Casein Kinase 2, Synergizes with B Cell Receptor Signaling Inhibitors in Inducing Diffuse Large B Cell Lymphoma Cell Death

Mandato, Elisa; Nunes, Sara Canovas; Zaffino, Fortunato; Casellato, Alessandro; Macaccaro, Paolo; Tubi, Laura Quotti; Visentin, Andrea; Trentin, Livio; Semenzato, Gianpietro

doi:10.2174/1568009617666170427110450

Cited by 10 publications

(7 citation statements)

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“…Hazan-Haley et al [35] first demonstrated that in CLL STAT3 is constitutively phosphorylated on Ser727, regardless of clinical parameters, being translocated into the nucleus by the karyopherin-beta nucleocytoplasmic system and bound to p21 and c-Myc genes. Serine phosphorylation of STAT3 is regulated by an aberrant cytoplasmic complex of CD5, BLNK, and CK2 (a pleiotropic serine/threonine kinase [36]) [37]. Moreover, it has been published that both IL-6, through the recruitment of JAK2, and the BCR, through a JAK2-independent mechanism, can promote STAT3 phosphorylation on Tyr705 [38].…”

Section: Discussionmentioning

confidence: 99%

In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment

Severin

Frezzato

Visentin

et al. 2019

Cancers

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The bone marrow microenvironment promotes proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Although ibrutinib is active in CLL, it is rarely able to clear leukemic cells protected by bone marrow mesenchymal stromal cells (BMSCs) within the marrow niche. We investigated the modulation of JAK2/STAT3 pathway in CLL by BMSCs and its targeting with AG490 (JAK2 inhibitor) or Stattic (STAT3 inhibitor). B cells collected from controls and CLL patients, were treated with medium alone, ibrutinib, JAK/Signal Transducer and Activator of Transcription (STAT) inhibitors, or both drugs, in the presence of absence of BMSCs. JAK2/STAT3 axis was evaluated by western blotting, flow cytometry, and confocal microscopy. We demonstrated that STAT3 was phosphorylated in Tyr705 in the majority of CLL patients at basal condition, and increased following co-cultures with BMSCs or IL-6. Treatment with AG490, but not Stattic, caused STAT3 and Lyn dephosphorylation, through re-activation of SHP-1, and triggered CLL apoptosis even when leukemic cells were cultured on BMSC layers. Moreover, while BMSCs hamper ibrutinib activity, the combination of ibrutinib+JAK/STAT inhibitors increase ibrutinib-mediated leukemic cell death, bypassing the pro-survival stimuli derived from BMSCs. We herein provide evidence that JAK2/STAT3 signaling might play a key role in the regulation of CLL-BMSC interactions and its inhibition enhances ibrutinib, counteracting the bone marrow niche.

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Section: Discussionmentioning

confidence: 99%

In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment

Severin

Frezzato

Visentin

et al. 2019

Cancers

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“…In another recent study, fostamatinib (which inhibits PLK1 as well as other serine-threonine kinases) was shown to be effective against the prostate cancer cell line (PC3) [102]. The anti-cancer activity of fostamatinib was also evident against head and neck squamous cell carcinoma [103], hepatocellular carcinoma [104], breast cancer [105], and diffuse large B cell lymphoma [106] cell lines. Moreover, a fostamatinib derivative, NSC765691, also exhibited antiproliferative activity against the panel of NCI-60 cell lines [107].…”

Section: Discussionmentioning

confidence: 98%

A Unified Transcriptional, Pharmacogenomic, and Gene Dependency Approach to Decipher the Biology, Diagnostic Markers, and Therapeutic Targets Associated with Prostate Cancer Metastasis

Bacolod

Barany

2021

Cancers

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This manuscript demonstrates how integrated bioinformatic and statistical reanalysis of publicly available genomic datasets can be utilized to identify molecular pathways and biomarkers that may be clinically relevant to metastatic prostate cancer (mPrCa) progression. The most notable observation is that the transition from primary prostate cancer to mPrCa is characterized by upregulation of processes associated with DNA replication, metastasis, and events regulated by the serine/threonine kinase PLK1. Moreover, our analysis also identified over-expressed genes that may be exploited for potential targeted therapeutics and minimally invasive diagnostics and monitoring of mPrCa. The primary data analyzed were two transcriptional datasets for tissues derived from normal prostate, primary prostate cancer, and mPrCa. Also incorporated in the analysis were the transcriptional, gene dependency, and drug response data for hundreds of cell lines, including those derived from prostate cancer tissues.

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“…CK2 was found overexpressed also in a panel of GC‐ and ABC‐type DLBCL cell lines and its inactivation with Silmitasertib caused apoptosis accompanied by a downmodulation of the CK2 phospho‐substrates CDC37 and NF‐κB p65/RelA . The following work has further investigated more in depth the consequences of CK2 inhibition with Silmitasertib on a panel of DLBCL cell lines, especially looking at signaling cascades emanating from the BCR and the synergy/cooperation with BCR signaling inhibitors . CK2 inhibition caused apoptosis of both GC‐ and ABC‐type DLBCL cells and a marked downregulation of the PI3K/AKT signaling cascade.…”

Section: Ck1 and Ck2 In Lymphoid Malignanciesmentioning

confidence: 94%

“…Moreover, the BCR signals were markedly impaired as judged by the dramatic down‐modulation of the spike of cytosolic Ca ++ concentration upon stimulation of the BCR. Intriguingly, equal cytotoxic activity was observed also in “double hit” lymphoma cells …”

Section: Ck1 and Ck2 In Lymphoid Malignanciesmentioning

confidence: 99%

New responsibilities for aged kinases in B‐lymphomas

Manni

Arjomand

Visentin

et al. 2019

Hematological Oncology

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The knowledge accumulated over the last decade on B-cell-derived non-Hodgkin lymphoma (B-NHL) pathogenesis has led to the identification of several molecular abnormalities, opening new perspectives in the design of novel therapies. Indeed, drugs targeting specific biochemical pathways critical for B-NHL cell survival, proliferation, and fitness within the malignant microenvironment are now available to the clinician: the B-cell receptor signaling inhibitors of BTK, PI3Kδ, ζ, γ, and SYK or the pro-apoptotic BH3-mimetics are clear examples of it. Moreover, it is emerging that malignant B-cell growth is sustained not only by mutations in oncogenes/tumor suppressors but also by the "addiction" to nononcogene (ie, nonstructurally altered) molecules. In this regard, a consistent body of data has established that the Ser/Thr kinases CK1, CK2, and GSK3 are involved in malignant lymphocyte biology and act as pro-survival and signaling-boosting molecules, both in precursor and mature B-cell tumors. Currently, an experimental and clinical groundwork is available, upon which to design CK1-, CK2-, and GSK3-directed antilymphoma/leukemia therapies. In this review, we have examined the main features of CK1, CK2, and GSK3 kinases, summarized the data in B-NHL supporting them as suitable therapeutic targets, and proposed a perspective on potential future research development. K E Y W O R D S B lymphocytes, CK1, CK2, GSK3, lymphoma, protein kinase 1 | EVOLVING PARADIGMS IN NON-HODGKIN LYMPHOMAS Non-Hodgkin lymphomas (NHL) are collectively the most frequent hematologic cancer, among the top 10 most frequent malignant tumors worldwide. 1 B-cell-derived NHL (B-NHL) are by far more frequent than T-cell-derived NHL, and between them, tumors arising from the mature B cell are more frequent. The 2016 World Health Organization (WHO) classification of NHL has recognized approximately 60 distinct entities. 2 In the group of B-NHL, diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype, accounting for 35% of all B-NHL, followed by follicular lymphoma (FL), which accounts for up to 20% to 25% of B-NHL. These two B-NHL subtypes originate from germinal center (GC) centrocytes/centroblasts. 3 However, a proportion of DLBCL are from post-GC origin, the so called "activated B-cell" (ABC)-type DLBCL. Patients affected by this latter subtype are believed to be subjected to a more dismal prognosis as compared with those with GC B-cell (GCB) type. 4 Other less frequent B-NHL are mantle cell lymphoma (MCL, approximately 10% of all B-NHL), marginal zone lymphoma (MZL, about 5% of all B-NHL), small lymphocyte lymphoma/chronic lymphocytic leukemia (SLL/CLL, 5%), lymphoplasmacytic lymphoma (LPL, 3%). 2 Deep sequencing of the genome and the transcriptome has provided a great amount of data describing mutations and aberrant expression of cell signaling molecules. For instance, the molecular classification of DLBCL has been progressively refined from the seminal paper of Alizadeh describing the GCB/ABC/undetermined subtypes, 4 based on gene expres...

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CX-4945, a Selective Inhibitor of Casein Kinase 2, Synergizes with B Cell Receptor Signaling Inhibitors in Inducing Diffuse Large B Cell Lymphoma Cell Death

Abstract: These findings suggest a role for CK2 downstream of the BCR in controlling survival pathways crucial for cell growth of different DLBCL subtypes. Also, the use of CX-4945 in combination with BCR signaling blockers could represent a novel rational therapeutic approach in the DLBCL.

Cited by 10 publications

References 0 publications

In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment

In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment

A Unified Transcriptional, Pharmacogenomic, and Gene Dependency Approach to Decipher the Biology, Diagnostic Markers, and Therapeutic Targets Associated with Prostate Cancer Metastasis

New responsibilities for aged kinases in B‐lymphomas

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