Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

Zhang, Meili; Griner, Lesley A. Mathews; Wang, Ju; Duveau, Damien Y.; Guha, Rajarshi; Petrus, Michael; Wen, Bernard; Maeda, Masako; Shinn, Paul; Ferrer, Marc; Conlon, Kevin; Bamford, Richard N.; O’Shea, John J.; Thomas, Craig J.; Waldmann, Thomas A.

doi:10.1073/pnas.1516208112

Cited by 80 publications

(88 citation statements)

References 37 publications

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“…19, 20, 21 The compounds tested included Carfilzomib (a proteasome inhibitor), Bardoxolone methyl (a KEAP inhibitor that inhibits the NFkB pathway), Navitoclax (a BCL2 inhibitor) and LLL-12 (a STAT3 inhibitor) (see Figure 3c for single-agent dose responses in all cell assay modes). In addition, one of the most potent and pan-active hits from the screens was Digoxin, an approved drug of the cardiac glycoside (CG) class (Supplementary Figure 3), and was also included in the combination screening.…”

Section: Resultsmentioning

confidence: 99%

“…19, 20, 21 The library includes approved drugs, compounds in clinical development for cancer treatment and compounds in pre-clinical development. In addition, where feasible, the library included several compounds for each target class or cellular mechanism and process.…”

Section: Methodsmentioning

confidence: 99%

“…13, 14, 15, 16, 17, 18 Both pancreatic and kidney cancers are aggressive, develop metastatic tumors and have characteristic markers of CSCs with very few treatment options. Using these newly developed HTS amenable assays, we screened an oncology-focused, mechanistically annotated library of 1912 chemotherapeutic agents 19, 20, 21 to find new drugs and/or drug combinations that cause death of these cells in 3D spheres or cells forming spheres. This library embraced mechanistic redundancy for the mechanism of action of the compounds, thus enabling the analysis of the results for target and pathway enrichment.…”

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confidence: 99%

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Large-scale pharmacological profiling of 3D tumor models of cancer cells

et al. 2016

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The discovery of chemotherapeutic agents for the treatment of cancer commonly uses cell proliferation assays in which cells grow as two-dimensional (2D) monolayers. Compounds identified using 2D monolayer assays often fail to advance during clinical development, most likely because these assays do not reproduce the cellular complexity of tumors and their microenvironment in vivo. The use of three-dimensional (3D) cellular systems have been explored as enabling more predictive in vitro tumor models for drug discovery. To date, small-scale screens have demonstrated that pharmacological responses tend to differ between 2D and 3D cancer cell growth models. However, the limited scope of screens using 3D models has not provided a clear delineation of the cellular pathways and processes that differentially regulate cell survival and death in the different in vitro tumor models. Here we sought to further understand the differences in pharmacological responses between cancer tumor cells grown in different conditions by profiling a large collection of 1912 chemotherapeutic agents. We compared pharmacological responses obtained from cells cultured in traditional 2D monolayer conditions with those responses obtained from cells forming spheres versus cells already in 3D spheres. The target annotation of the compound library screened enabled the identification of those key cellular pathways and processes that when modulated by drugs induced cell death in all growth conditions or selectively in the different cell growth models. In addition, we also show that many of the compounds targeting these key cellular functions can be combined to produce synergistic cytotoxic effects, which in many cases differ in the magnitude of their synergism depending on the cellular model and cell type. The results from this work provide a high-throughput screening framework to profile the responses of drugs both as single agents and in pairwise combinations in 3D sphere models of cancer cells.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Large-scale pharmacological profiling of 3D tumor models of cancer cells

et al. 2016

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“…In this model, there was an additive or synergistic effect with ruxolitinib and either navitoclax, panobinstat, and mTOR, PI3K, or NFkB inhibitors. Combining ruxolitinib and navitoclax resulted a significant decrease in tumor burden and in prolonged survival in an ATL mouse model [95]. …”

Section: Potential Obstacles With Jak Inhibitor Therapy and Suggesmentioning

confidence: 99%

The promise of Janus kinase inhibitors in the treatment of hematological malignancies

Senkevitch

Durum

2017

Cytokine

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The Janus kinases (JAK) are a family of kinases that play an essential role in cytokine signaling and are implicated in the pathogenesis of autoimmune diseases and hematological malignancies. As a result, the JAKs have become attractive therapeutic targets. The discovery of a JAK2 point mutation (JAK2 V617F) as the main cause of polycythemia vera lead to the development and FDA approval of a JAK1/2 inhibitor, ruxolitinib, in 2011. This review focuses on the various JAK and associated components aberrations implicated in myeloproliferative neoplasms, leukemias, and lymphomas. In addition to ruxolitinib, other JAK inhibitors are currently being evaluated in clinical trials for treating hematological malignancies. The use of JAK inhibitors alone or in combination therapy should be considered as a way to deliver targeted therapy to patients.

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“…To address this issue using a matrix-screening platform we evaluated ruxolitinib within a dose response matrix experiment with > 450 approved or investigational agents (Zhang, et al, 2015). Additive/synergistic effects were demonstrated in the IL-2 dependent ED40515 (+) cell line with ruxolitinib when combined with the inhibitors Bcl-2/Bcl-xL (navitoclax), HDACs (panobinostat, pracinostat), mTORC1/2 (AZD-8055), Aurora A/B/C/kinases (AMG 900), PI3Ks (GSK2126458) and NF-κB/IKK (Withaferin A, SPC-839, bardoxolone methyl).…”

Section: Introductionmentioning

confidence: 99%

JAK/STAT pathway directed therapy of T-cell leukemia/lymphoma: Inspired by functional and structural genomics

Waldmann

2017

Molecular and Cellular Endocrinology

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Abnormal activation of the γc cytokine JAK/STAT signaling pathway assessed by STAT3 or STAT5b phosphorylation was present in a proportion of many T-cell malignancies. Activating mutations of STAT3/STAT5b and JAK1/3 were present in some but not in all cases with constitutive signaling pathway activation. Using shRNA analysis pSTAT malignant T-cell lines were addicted to JAKs/STATs whether they were mutated or not. Activating JAK/STAT mutations were not sufficient to support leukemic cell proliferation but only augmented upstream pathway signals. Functional cytokine receptors were required for pSTAT expression. Combining a JAK1/2 inhibitor with a Bcl-xL inhibitor navitoclax provided additive/synergistic activity with IL-2 dependent ATLL cell lines and in a mouse model of human IL-2 dependent ATLL. The insight that disorders of the γc/JAK/STAT system are pervasive suggests approaches including those that target gamma cytokines, their receptors or that use JAK kinase inhibitors may be of value in multicomponent therapy for T-cell malignancies.

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Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

Cited by 80 publications

References 37 publications

Large-scale pharmacological profiling of 3D tumor models of cancer cells

Large-scale pharmacological profiling of 3D tumor models of cancer cells

The promise of Janus kinase inhibitors in the treatment of hematological malignancies

JAK/STAT pathway directed therapy of T-cell leukemia/lymphoma: Inspired by functional and structural genomics

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