ArticleScience signaling2014
RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis.
Article in Science signaling, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 77 citations in OpenAlex.
- Addition of Navitoclax to Ongoing Ruxolitinib Therapy for Patients With Myelofibrosis With Progression or Suboptimal Response: Phase II Safety and Efficacy.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2022Trial
- BAK is a predictive and prognostic biomarker for the therapeutic effect of docetaxel treatment in patients with advanced gastric cancer.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2016Trial
- Clinical implications of RAS mutations in AML: prognostic significance is based upon the involved gene and mutation complexity.Blood advances · 2026Article
- Revealing miRNAs' Janus-Faced Nature: Transforming Cold Tumours into Immunotherapy Hotspots and Overcoming Chemoresistance.MicroRNA (Shariqah, United Arab Emirates) · 2026Review
- JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms.Nature communications · 2025Article
- Malignant JAK-signaling: at the interface of inflammation and malignant transformation.Leukemia · 2025Review
- Mutational cooperativity of RUNX1::RUNX1T1 isoform 9a and oncogenic NRAS in zebrafish myeloid leukaemia.Biology open · 2024Article
- SHP2 inhibition displays efficacy as a monotherapy and in combination with JAK2 inhibition in preclinical models of myeloproliferative neoplasms.American journal of hematology · 2024Article
- RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives.Blood cancer journal · 2024Review
- Concurrent inhibition of pBADS99 synergistically improves MEK inhibitor efficacy in KRASCell death & disease · 2024Article
- Molecular biomarkers of leukemia: convergence-based drug resistance mechanisms in chronic myeloid leukemia and myeloproliferative neoplasms.Frontiers in pharmacology · 2024Review
- Type II mode of JAK2 inhibition and destabilization are potential therapeutic approaches against the ruxolitinib resistance driven myeloproliferative neoplasms.Frontiers in oncology · 2024Article
- BCR::ABL1-like acute lymphoblastic leukaemia: a single institution experience on identification of potentially therapeutic targetable cases.Molecular cytogenetics · 2023Article
- Review
- Exploiting endogenous and therapy-induced apoptotic vulnerabilities in immunoglobulin light chain amyloidosis with BH3 mimetics.Nature communications · 2022Article
- Mechanisms of resistance to targeted therapies for relapsed or refractory acute myeloid leukemia.Experimental hematology · 2022Review
- Apoptosis: Directly Targeted at Last.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2022Article
- Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics.Cancer discovery · 2022Review
- Understanding Aberrant Signaling to Elude Therapy Escape Mechanisms in Myeloproliferative Neoplasms.Cancers · 2022Review
- JAK2 inhibitor persistence in MPN: uncovering a central role of ERK activation.Blood cancer journal · 2022Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Myeloproliferative neoplasms (MPNs) frequently have an activating mutation in the gene encoding Janus kinase 2 (JAK2). Thus, targeting the pathway mediated by JAK and its downstream substrate, signal transducer and activator of transcription (STAT), may yield clinical benefit for patients with MPNs containing the JAK2(V617F) mutation. Although JAK inhibitor therapy reduces splenomegaly and improves systemic symptoms in patients, this treatment does not appreciably reduce the number of neoplastic cells. To identify potential mechanisms underlying this inherent resistance phenomenon, we performed pathway-centric, gain-of-function screens in JAK2(V617F) hematopoietic cells and found that the activation of the guanosine triphosphatase (GTPase) RAS or its effector pathways [mediated by the kinases AKT and ERK (extracellular signal-regulated kinase)] renders cells insensitive to JAK inhibition. Resistant MPN cells became sensitized to JAK inhibitors when also exposed to inhibitors of the AKT or ERK pathways. Mechanistically, in JAK2(V617F) cells, a JAK2-mediated inactivating phosphorylation of the proapoptotic protein BAD [B cell lymphoma 2 (BCL-2)-associated death promoter] promoted cell survival. In sensitive cells, exposure to a JAK inhibitor resulted in dephosphorylation of BAD, enabling BAD to bind and sequester the prosurvival protein BCL-XL (BCL-2-like 1), thereby triggering apoptosis. In resistant cells, RAS effector pathways maintained BAD phosphorylation in the presence of JAK inhibitors, yielding a specific dependence on BCL-XL for survival. In patients with MPNs, activating mutations in RAS co-occur with the JAK2(V617F) mutation in the malignant cells, suggesting that RAS effector pathways likely play an important role in clinically observed resistance.
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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.