Reference Detail

Ref Type Journal Article
PMID (21393331)
Authors Hornakova T, Springuel L, Devreux J, Dusa A, Constantinescu SN, Knoops L, Renauld JC
Title Oncogenic JAK1 and JAK2-activating mutations resistant to ATP-competitive inhibitors.
Journal Haematologica
Vol 96
Issue 6
Date 2011 Jun
URL
Abstract Text Activating mutations in JAK1 and JAK2 have been described in patients with various hematologic malignancies including acute lymphoblastic leukemia and myeloproliferative neoplasms, leading to clinical trials with JAK inhibitors. While there has been a tremendous effort towards the development of specific JAK inhibitors, mutations conferring resistance to such drugs have not yet been observed.Taking advantage of a model of spontaneous cellular transformation, we sequenced JAK1 in selected tumorigenic BaF3 clones and identified 25 de novo JAK1 activating mutations, including 5 mutations already described in human leukemias. We further used this library of JAK1 mutation-positive cell lines to assess their sensitivity to ATP-competitive inhibitors.While most JAK1 mutants were sensitive to ATP-competitive JAK inhibitors, mutations targeting Phe958 and Pro960 in the hinge region of the kinase domain rendered JAK1 constitutively active but also resistant to all tested JAK inhibitors. Furthermore, mutation of the homologous Tyr931 in JAK2 wild-type or JAK2 V617F mutant found in patients with myeloproliferative neoplasms also conferred resistance to JAK inhibitors, such as INCB018424, which is currently in clinical use.Our data indicate that some activating mutations not only promote autonomous cell proliferation but also confer resistance to ATP-competitive inhibitors. In vivo, such a mutation can potentially occur as primary JAK-activating mutations but also as secondary mutations combining oncogenicity with drug resistance.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Y931C missense gain of function JAK2 Y931C lies within the JH1 protein kinase domain 2 of the Jak2 protein (UniProt.org, PMID: 21393331). Y931C results in increased Jak2 kinase activity (PMID: 21393331) and is transforming in cell culture (PMID: 21393331, PMID: 26419724).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK2 V617F JAK2 Y931C cancer resistant Ruxolitinib Preclinical Actionable In a preclinical study, cells harboring the JAK2 V617F/Y931C double mutation displayed resistance to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). 21393331
JAK2 Y931C cancer resistant Ruxolitinib Preclinical Actionable In a preclinical study, cells harboring JAK2 Y931C displayed resistance to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). 21393331