ArticleThe Journal of experimental medicine2012
Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition.
Article in The Journal of experimental medicine, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 97 papers.
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Who cites it
97 citing papers in PubMed, 162 citations in OpenAlex.
- Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias.Blood · 2015Trial
- Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth.The Journal of clinical investigation · 2014Trial
- The Mechanisms of Resistance to JAK Inhibitors in Lymphoid Leukemias: A Scoping Review of Evidence from Preclinical Models and Case Reports.International journal of molecular sciences · 2025Article
- JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms.Nature communications · 2025Article
- Review
- Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling.Nature communications · 2025Article
- A newly identified 45-kDa JAK2 variant with an altered kinase domain structure represents a novel mode of JAK2 kinase inhibitor resistance.Molecular oncology · 2024Article
- Type II mode of JAK2 inhibition and destabilization are potential therapeutic approaches against the ruxolitinib resistance driven myeloproliferative neoplasms.Frontiers in oncology · 2024Article
- PU-H71 (NSC 750424): a molecular masterpiece that targets HSP90 in cancer and beyond.Frontiers in pharmacology · 2024Review
- New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation.Cell chemical biology · 2023Article
- Heat-Shock Proteins in Leukemia and Lymphoma: Multitargets for Innovative Therapeutic Approaches.Cancers · 2023Review
- BCL6 inhibition ameliorates resistance to ruxolitinib inHaematologica · 2023Article
- Role of JAK inhibitors in myeloproliferative neoplasms: current point of view and perspectives.International journal of hematology · 2022Review
- Review
- Combination efficacy of ruxolitinib with standard-of-care drugs in CRLF2-rearranged Ph-like acute lymphoblastic leukemia.Leukemia · 2021Article
- Recent Advances in Molecular Diagnostics and Targeted Therapy of Myeloproliferative Neoplasms.Cancers · 2021Review
- Network Analysis Reveals Synergistic Genetic Dependencies for Rational Combination Therapy in Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia.NPJ precision oncology · 2021Article
- Novel Pathophysiological Mechanisms of Thrombosis in Myeloproliferative Neoplasms.Current hematologic malignancy reports · 2021Review
- HSP90 inhibitor NVP-BEP800 affects stability of SRC kinases and growth of T-cell and B-cell acute lymphoblastic leukemias.Blood cancer journal · 2021Article
37 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
31 authors at 7 institutions in 3 countries.
Funding
Abstract
Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor-like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with JAK2 V617F (observed in MPNs) or JAK2 R683G (observed in B-ALL). G935R, Y931C, and E864K do not reduce the sensitivity of JAK2-dependent cells to inhibitors of heat shock protein 90 (HSP90), which promote the degradation of both wild-type and mutant JAK2. HSP90 inhibitors were 100-1,000-fold more potent against CRLF2-rearranged B-ALL cells, which correlated with JAK2 degradation and more extensive blockade of JAK2/STAT5, MAP kinase, and AKT signaling. In addition, the HSP90 inhibitor AUY922 prolonged survival of mice xenografted with primary human CRLF2-rearranged B-ALL further than an enzymatic JAK2 inhibitor. Thus, HSP90 is a promising therapeutic target in JAK2-driven cancers, including those with genetic resistance to JAK enzymatic inhibitors.
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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.