ArticleOncotarget2015
The PIM inhibitor AZD1208 synergizes with ruxolitinib to induce apoptosis of ruxolitinib sensitive and resistant JAK2-V617F-driven cells and inhibit colony formation of primary MPN cells.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 38 citations in OpenAlex.
- PIM1 in myeloproliferative neoplasms: potential pathogenic and therapeutic implications.Leukemia · 2026Review
- JAK2V617F reprograms Hypoxia Inducible Factor-1 to induce a non-canonical hypoxia regulon in myeloproliferative neoplasms.Leukemia · 2026Article
- SHP2 inhibition displays efficacy as a monotherapy and in combination with JAK2 inhibition in preclinical models of myeloproliferative neoplasms.American journal of hematology · 2024Article
- An overview of pim kinase as a target in multiple myeloma.Cancer medicine · 2023Review
- Targeting Pim kinases in hematological cancers: molecular and clinical review.Molecular cancer · 2023Review
- Novel strategies for challenging scenarios encountered in managing myelofibrosis.Leukemia & lymphoma · 2022Article
- Article
- Understanding Aberrant Signaling to Elude Therapy Escape Mechanisms in Myeloproliferative Neoplasms.Cancers · 2022Review
- Therapeutic Efficacy of Combined JAK1/2, Pan-PIM, and CDK4/6 Inhibition in Myeloproliferative Neoplasms.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms.International journal of molecular sciences · 2021Review
- Bcl-xL represents a therapeutic target in Philadelphia negative myeloproliferative neoplasms.Journal of cellular and molecular medicine · 2020Article
- Finding a Jill for JAK: Assessing Past, Present, and Future JAK Inhibitor Combination Approaches in Myelofibrosis.Cancers · 2020Review
- Human papillomavirus insertions identify the PIM family of serine/threonine kinases as targetable driver genes in head and neck squamous cell carcinoma.Cancer letters · 2020Article
- PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer.Signal transduction and targeted therapy · 2020Review
- HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms.Blood · 2020Article
- The pan-PIM inhibitor INCB053914 displays potent synergy in combination with ruxolitinib in models of MPN.Blood advances · 2019Article
- Curcumin induces apoptosis in JAK2-mutated cells by the inhibition of JAK2/STAT and mTORC1 pathways.Journal of cellular and molecular medicine · 2019Article
- New Concepts of Treatment for Patients with Myelofibrosis.Current treatment options in oncology · 2019Review
- Advances in potential treatment options for myeloproliferative neoplasm associated myelofibrosis.Expert opinion on orphan drugs · 2019Article
- The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms.Journal of translational medicine · 2018Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Classical myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders that exhibit excess mature myeloid cells, bone marrow fibrosis, and risk of leukemic transformation. Aberrant JAK2 signaling plays an etiological role in MPN formation. Because neoplastic cells in patients are largely insensitive to current anti-JAK2 therapies, effective therapies remain needed. Members of the PIM family of serine/threonine kinases are induced by JAK/STAT signaling, regulate hematopoietic stem cell growth, protect hematopoietic cells from apoptosis, and exhibit hematopoietic cell transforming properties. We hypothesized that PIM kinases may offer a therapeutic target for MPNs. We treated JAK2-V617F-dependent MPN model cells as well as primary MPN patient cells with the PIM kinase inhibitors SGI-1776 and AZD1208 and the JAK2 inhibitor ruxolitinib. While MPN model cells were rather insensitive to PIM inhibitors, combination of PIM inhibitors with ruxolitinib led to a synergistic effect on MPN cell growth due to enhanced apoptosis. Importantly, PIM inhibitor mono-therapy inhibited, and AZD1208/ruxolitinib combination therapy synergistically suppressed, colony formation of primary MPN cells. Enhanced apoptosis by combination therapy was associated with activation of BAD, inhibition of downstream components of the mTOR pathway, including p70S6K and S6 protein, and activation of 4EBP1. Importantly, PIM inhibitors re-sensitized ruxolitinib-resistant MPN cells to ruxolitinib by inducing apoptosis. Finally, exogenous expression of PIM1 induced ruxolitinib resistance in MPN model cells. These data indicate that PIMs may play a role in MPNs and that combining PIM and JAK2 kinase inhibitors may offer a more efficacious therapeutic approach for MPNs over JAK2 inhibitor mono-therapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.