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	Vol	Issue	Date	Pages	Journal Short Title
Haematologica	96	6	2011 Jun	845-53	Haematologica

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	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
JAK2	Y931C	missense	gain of function	JAK2 Y931C lies within the protein kinase domain 2 of the Jak2 protein (UniProt.org). Y931C results in increased phosphorylation of Jak2 and Stat5, is transforming in cell culture, and confers resistance to Jak inhibitors (PMID: 21393331, PMID: 26419724).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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