Dual PI3K/AKT/mTOR Inhibitor BEZ235 Synergistically Enhances the Activity of JAK2 Inhibitor against Cultured and Primary Human Myeloproliferative Neoplasm Cells

Fiskus, Warren; Verstovšek, Srđan; Manshouri, Taghi; Smith, Jacqueline E.; Peth, Karissa; Abhyankar, Sunil; McGuirk, Joseph P.; Bhalla, Kapil N.

doi:10.1158/1535-7163.mct-12-0862

Cited by 95 publications

(70 citation statements)

References 54 publications

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“…Banked, delinked, and deidentified, normal or AML CD34 þ or AML CD34 þ CD38-LIN À bone marrow progenitor/stem cells were purified, as previously described (18). The clinical presentation of the patient and mutation status of the primary AML samples used in these studies is provided in Supplementary Table S1.…”

Section: Primary Normal Progenitor and Aml Bpcsmentioning

confidence: 99%

“…In previous reports, we demonstrated that treatment with hydroxamic acid analog pan-histone deacetylase (HDAC) inhibitors, such as panobinostat (LBH589), induces hyperacetylation of histones as well as mediates growth arrest and apoptosis of cultured and primary AML cells (17,18). Concomitantly, panobinostat treatment attenuated the levels of progrowth and prosurvival proteins, for example, BCL2 and c-MYC, while simultaneously inducing the levels of proapoptotic protein BIM (17)(18)(19).…”

Section: Introductionmentioning

confidence: 98%

“…Concomitantly, panobinostat treatment attenuated the levels of progrowth and prosurvival proteins, for example, BCL2 and c-MYC, while simultaneously inducing the levels of proapoptotic protein BIM (17)(18)(19). On the basis of these observations, we hypothesized that the lysine hyperacetylation induced by treatment with panobinostat would increase the dependency of AML cells on BET protein-regulated transcription of the oncogenes c-MYC and BCL2, such that this would make the AML cells especially susceptible to the activity of the BET (BRD4/2) protein antagonist JQ1.…”

Section: Introductionmentioning

confidence: 99%

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Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

Fiskus

Sharma

et al. 2014

Molecular Cancer Therapeutics

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170

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The bromodomain and extra-terminal (BET) protein family members, including BRD4, bind to acetylated lysines on histones and regulate the expression of important oncogenes, for example, c-MYC and BCL2. Here, we demonstrate the sensitizing effects of the histone hyperacetylation-inducing pan-histone deacetylase (HDAC) inhibitor panobinostat on human acute myelogenous leukemia (AML) blast progenitor cells (BPC) to the BET protein antagonist JQ1. Treatment with JQ1, but not its inactive enantiomer (R-JQ1), was highly lethal against AML BPCs expressing mutant NPM1cþ with or without coexpression of FLT3-ITD or AML expressing mixed lineage leukemia fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of c-MYC and BCL2 and reduced their levels in the AML cells. Cotreatment with JQ1 and the HDAC inhibitor panobinostat synergistically induced apoptosis of the AML BPCs, but not of normal CD34 þ hematopoietic progenitor cells. This was associated with greater attenuation of c-MYC and BCL2, while increasing p21, BIM, and cleaved PARP levels in the AML BPCs. Cotreatment with JQ1 and panobinostat significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (P < 0.01). These findings highlight cotreatment with a BRD4 antagonist and an HDAC inhibitor as a potentially efficacious therapy of AML. Mol Cancer Ther; 13(5); 1142-54. Ó2014 AACR.

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Section: Primary Normal Progenitor and Aml Bpcsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

Fiskus

Sharma

et al. 2014

Molecular Cancer Therapeutics

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170

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“…Combining different therapies against multiple ‘oncogene addictions’ could be a possibility to overcome primary or acquired resistance. Targeted approaches in solid cancers inhibit common downstream mediators of known oncogenes, such as MEK-ERK or the PI3K-AKT-mTOR kinase pathways, and similar pathways may also play a role in oncogenesis in hematopoietic malignancies [13]. Last, newer therapeutic strategies aim to exploit the specific dependency of cancer cells on basic cellular processes such as cell division, chromatin regulation, and metabolism.…”

Section: Identification Of Key Driver Mutations In Hematopoietic Cancermentioning

confidence: 99%

“…It was shown through genetic experiments that particularly the activation of the two STAT5 transcription factors is crucial for PV [20]. Hyperactive JAK2 promotes prominent activation of the PI3K-AKT-mTOR and the RAS-RAF/MAPK-ERK pathways, among other less prominent signaling pathways, and evades negative-regulation by SOCS proteins [13]. …”

Section: Targets In Mpn and Driver Mutationsmentioning

confidence: 99%

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

Orlova

Wingelhofer

Neubauer

et al. 2017

Expert Opinion on Therapeutic Targets

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Introduction: Hematopoietic neoplasms are often driven by gain-of-function mutations of the JAK-STAT pathway together with mutations in chromatin remodeling and DNA damage control pathways. The interconnection between the JAK-STAT pathway, epigenetic regulation or DNA damage control is still poorly understood in cancer cell biology. Areas covered: Here, we focus on a broader description of mutational insights into myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas, since sequencing efforts have identified similar combinations of driver mutations in these diseases covering different lineages. We summarize how these pathways might be interconnected in normal or cancer cells, which have lost differentiation capacity and drive oncogene transcription. Expert opinion: Due to similarities in driver mutations including epigenetic enzymes, JAK-STAT pathway activation and mutated checkpoint control through TP53, we hypothesize that similar therapeutic approaches could be of benefit in these diseases. We give an overview of how driver mutations in these malignancies contribute to hematopoietic cancer initiation or progression, and how these pathways can be targeted with currently available tools.

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IL‐6 stimulation of DNA replication is JAK1/2 mediated in cross‐talk with hyperactivated ERK1/2 signaling

Subotički

Ajtić

Beleslin-Čokić

et al. 2019

Cell Biology International

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Myeloproliferative neoplasms (MPNs) are developing resistance to therapy by JAK1/2 inhibitor ruxolitinib. To explore the mechanism of ruxolitinib's limited effect, we examined the JAK1/2 mediated induction of proliferation related ERK1/2 and AKT signaling by proinflammatory interleukin-6 (IL-6) in MPN granulocytes and JAK2V617F mutated human erythroleukemia (HEL) cells. We found that JAK1/2 or JAK2 inhibition prevented the IL-6 activation of STAT3 and AKT pathways in polycythemia vera and HEL cells. Further, we showed that these inhibitors also blocked the IL-6 activation of the AKT pathway in primary myelofibrosis (PMF). Only JAK1/2 inhibitor ruxolitinib largely activated ERK1/2 signaling in essential thrombocythemia and PMF (up to 4.6 fold), with a more prominent activation in JAK2V617F positive granulocytes. Regarding a cell cycle, we found that IL-6 reduction of HEL cells percentage in G2M phase was reversed by ruxolitinib (2.6 fold). Moreover, ruxolitinib potentiated apoptosis of PMF granulocytes (1.6 fold). Regarding DNA replication, we found that ruxolitinib prevented the IL-6 augmentation of MPN granulocytes frequency in the S phase of the cell cycle (up to 2.9 fold). The inflammatory stimulation induces a cross-talk between the proliferation linked pathways, where JAK1/2 inhibition is compensated by the activation of the ERK1/2 pathway during IL-6 stimulation of DNA replication.

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Dual PI3K/AKT/mTOR Inhibitor BEZ235 Synergistically Enhances the Activity of JAK2 Inhibitor against Cultured and Primary Human Myeloproliferative Neoplasm Cells

Abstract: Hemopoietic progenitor cells

Cited by 95 publications

References 54 publications

Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

IL‐6 stimulation of DNA replication is JAK1/2 mediated in cross‐talk with hyperactivated ERK1/2 signaling

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