ArticleJournal of cellular and molecular medicine2013
Co-targeting the PI3K/mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms.
Article in Journal of cellular and molecular medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
63 citing papers in PubMed, 136 citations in OpenAlex.
- Add-on parsaclisib for patients with myelofibrosis and suboptimal response to ruxolitinib: a randomized phase 3 study.The oncologist · 2026Trial
- Phase 2 study of add-on parsaclisib for patients with myelofibrosis and suboptimal response to ruxolitinib: final results.Blood advances · 2024Trial
- Roginolisib in Combination with JAK Inhibitors in Patients with Myelofibrosis Who are Unresponsive to Approved JAK Inhibitors (Study HEMA-MED) - A Trial in Progress.OncoTargets and therapy · 2026Article
- Differential regulation of mTORC2 signalling by type I and type II calreticulin (CALR) driver mutations of myeloproliferative neoplasm.Cell communication and signaling : CCS · 2025Article
- JAK Inhibitors for Myelofibrosis: Strengths and Limitations.Current hematologic malignancy reports · 2024Review
- A review on the functional characteristics of the c-Myeloproliferative Leukaemia (c-MPL) gene and its isoforms.Cellular oncology (Dordrecht, Netherlands) · 2024Review
- The Role of Mutated Calreticulin in the Pathogenesis ofInternational journal of molecular sciences · 2024Article
- Lysosomal degradation targets mutant calreticulin and the thrombopoietin receptor in myeloproliferative neoplasms.Blood advances · 2024Article
- Platelet proteo-transcriptomic profiling validates mediators of thrombosis and proteostasis in patients with myeloproliferative neoplasms.bioRxiv : the preprint server for biology · 2023Article
- Inhibition of ERK1/2 signaling prevents bone marrow fibrosis by reducing osteopontin plasma levels in a myelofibrosis mouse model.Leukemia · 2023Article
- SOHO State of the Art Updates and Next Questions: Novel Therapeutic Strategies in Development for Myelofibrosis.Clinical lymphoma, myeloma & leukemia · 2023Review
- Inflammation Promotes Oxidative and Nitrosative Stress in Chronic Myelogenous Leukemia.Biomolecules · 2022Article
- JAK2 inhibitor persistence in MPN: uncovering a central role of ERK activation.Blood cancer journal · 2022Review
- Dnmt3a is downregulated by Stat5a and mediates G0/G1 arrest by suppressing the miR-17-5p/Cdkn1a axis in Jak2BMC cancer · 2021Article
- Recent Advances in Molecular Diagnostics and Targeted Therapy of Myeloproliferative Neoplasms.Cancers · 2021Review
- Integration of Molecular Information in Risk Assessment of Patients with Myeloproliferative Neoplasms.Cells · 2021Review
- JAK Be Nimble: Reviewing the Development of JAK Inhibitors and JAK Inhibitor Combinations for Special Populations of Patients with Myelofibrosis.Journal of immunotherapy and precision oncology · 2021Review
- VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms.International journal of molecular sciences · 2021Article
- Review
- The delta isoform of phosphatidylinositol-3-kinase predominates in chronic myelomonocytic leukemia and can be targeted effectively with umbralisib and ruxolitinib.Experimental hematology · 2021Article
3 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aberrant JAK2 signalling plays a central role in myeloproliferative neoplasms (MPN). JAK2 inhibitors have proven to be clinically efficacious, however, they are not mutation-specific and competent enough to suppress neoplastic clonal haematopoiesis. We hypothesized that, by simultaneously targeting multiple activated signalling pathways, MPN could be more effectively treated. To this end we investigated the efficacy of BEZ235, a dual PI3K/mTOR inhibitor, alone and in combination with the JAK1/JAK2 inhibitor ruxolitinib, in different preclinical models of MPN. Single-agent BEZ235 inhibited the proliferation and induced cell cycle arrest and apoptosis of mouse and human JAK2V617F mutated cell lines at concentrations significantly lower than those required to inhibit the wild-type counterpart, and preferentially prevented colony formation from JAK2V617F knock-in mice and patients' progenitor cells compared with normal ones. Co-treatment of BEZ235 and ruxolitinib produced significant synergism in all these in-vitro models. Co-treatment was also more effective than single drugs in reducing the extent of disease and prolonging survival of immunodeficient mice injected with JAK2V617F-mutated Ba/F3-EPOR cells and in reducing spleen size, decreasing reticulocyte count and improving spleen histopathology in conditional JAK2V617F knock-in mice. In conclusion, combined inhibition of PI3K/mTOR and JAK2 signalling may represent a novel therapeutic strategy in MPN.
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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.