Missing content? – Request curation!
Request curation for specific Genes, Variants, or PubMed publications.
Have questions, comments, or suggestions? - Let us know!
Email us at : ckbsupport@genomenon.com
| 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. | ||||||||||||
|
|||||||||||||
| 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. | ||||||||||||
| 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 |
|---|---|---|---|---|---|
| JAK1 | A723D | missense | gain of function | JAK1 A723D lies within the protein kinase domain 1 of the Jak1 protein (UniProt.org). A723D results in constitutive phosphorylation of Jak1 and Stat5 in cell culture (PMID: 21393331, PMID: 24735922). | |
| JAK1 | D895H | missense | gain of function | JAK1 D895H lies within the protein kinase domain 2 of the Jak1 protein (UniProt.org). D895H results in constitutive Jak1 phosphorylation, increased phosphorylation of Stat5 and Erk in culture, and tumor formation in mouse models (PMID: 21393331). | |
| JAK1 | E897K | missense | gain of function - predicted | JAK1 E897K lies within protein kinase domain 2 of the Jak1 protein (UniProt). E897K results in constitutive Jak1 phosphorylation, and increased phosphorylation of Stat5 and Erk in culture (PMID: 21393331), and therefore, is predicted to lead a gain of Jak1 protein function. | |
| JAK1 | F635V | missense | gain of function | JAK1 F635V lies within the protein kinase domain 1 of the Jak1 protein (UniProt.org). F635V results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk, and is transforming in cell culture (PMID: 21393331). | |
| JAK1 | F734L | missense | gain of function - predicted | JAK1 F734L lies within protein kinase domain 1 of the Jak1 protein (UniProt.org). F734L results in constitutive Jak1 phosphorylation, and increased phosphorylation of Stat5 and Erk in culture (PMID: 21393331), and therefore, is predicted to lead a gain of Jak1 protein function. | |
| JAK1 | F958C | missense | gain of function | JAK1 F958C lies within the protein kinase domain 2 of the Jak1 protein (UniProt.org). F958C results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk, transformation of cultured cells, and confers resistance to Jak inhibitors in culture (PMID: 21393331). | Y |
| JAK1 | F958L | missense | gain of function - predicted | JAK1 F958L lies within protein kinase domain 2 of the Jak1 protein (UniProt.org). F958L results in constitutive Jak1 phosphorylation, increased phosphorylation of Stat5 and Erk in culture, and confers resistance to Jak inhibitors in culture (PMID: 21393331), and therefore, is predicted to lead to a gain of Jak1 protein function. | Y |
| JAK1 | F958S | missense | gain of function | JAK1 F958S lies within the protein kinase domain 2 of the Jak1 protein (UniProt.org). F958S results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk, transformation of cultured cells, and confers resistance to Jak inhibitors in culture (PMID: 21393331, PMID: 20868368). | Y |
| JAK1 | F958V | missense | gain of function | JAK1 F958V lies within the protein kinase domain 2 of the Jak1 protein (UniProt.org). F958V results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk, transformation of cultured cells, and tumor formation in mouse models, and confers resistance to Jak inhibitors in culture (PMID: 21393331). | Y |
| JAK1 | K1026E | missense | gain of function - predicted | JAK1 K1026E lies within protein kinase domain 2 of the Jak1 protein (UniProt.org). K1026E is transforming in culture and promotes tumor formation in mouse models, but results in variable phosphorylation levels of Jak1 and downstream signaling proteins in culture (PMID: 21393331, PMID: 20868368), and therefore, is predicted to lead to a gain of Jak1 protein function. | |
| JAK1 | L783F | missense | gain of function | JAK1 L783F lies within the protein kinase domain 1 of the Jak1 protein (UniProt.org). Y652H results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk, and is transforming in cell culture (PMID: 21393331). | |
| JAK1 | L910Q | missense | gain of function - predicted | JAK1 L910Q lies within protein kinase domain 2 of the Jak1 protein (UniProt.org). L910Q results in constitutive Jak1 phosphorylation and increased phosphorylation of Stat5 in culture (PMID: 21393331), and therefore, is predicted to lead to a gain of Jak1 protein function. | |
| JAK1 | P815S | missense | gain of function | JAK1 P815S lies within the protein kinase domain 1 of the Jak1 protein (UniProt.org). P815S results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk, and is transforming in cell culture (PMID: 21393331). | |
| JAK1 | P960S | missense | gain of function | JAK1 P960S lies within the protein kinase domain 2 of the Jak1 protein (UniProt.org). P960S results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk (PMID: 21393331), transformation of cultured cells (PMID: 20868368), and confers resistance to Jak inhibitors in culture (PMID: 21393331).. | Y |
| JAK1 | P960T | missense | gain of function | JAK1 P960T lies within the protein kinase domain 2 of the Jak1 protein (UniProt.org). P960T results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk, transformation of cultured cells, and confers resistance to Jak inhibitors in culture (PMID: 21393331). | Y |
| JAK1 | R724S | missense | gain of function | JAK1 R724S lies within the protein kinase domain 1 of the Jak1 protein (UniProt.org). R724S results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk, and is transforming in cell culture (PMID: 21393331). | |
| JAK1 | S1043I | missense | gain of function | JAK1 S1043I lies within the protein kinase domain 2 of the Jak1 protein (UniProt.org). S1043I results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk, transformation of cultured cells, and tumor formation in mouse models (PMID: 21393331). | |
| JAK1 | S646F | missense | gain of function | JAK1 S646F lies within the protein kinase domain 1 of the Jak1 protein (UniProt.org). S646F results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk, and is transforming in cell culture (PMID: 21393331, PMID: 21551237). | |
| JAK1 | S703I | missense | gain of function | JAK1 S703I lies within the protein kinase domain 1 of the Jak1 protein (UniProt.org). S703I results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk, and is transforming in cell culture (PMID: 24825865, PMID: 21393331). | |
| JAK1 | T901R | missense | gain of function | JAK1 T901R lies within the protein kinase domain 2 of the Jak1 protein (UniProt.org). T901R results in constitutive Jak1 phosphorylation, increased phosphorylation of Stat5 and Erk in culture (PMID: 21393331), and therefore, is predicted to lead a gain of Jak1 protein function. | |
| JAK1 | V658F | missense | gain of function | JAK1 V658F lies within the protein kinase domain 1 of the Jak1 protein (UniProt.org). V658F results in constitutive Jak1 activation, increased ligand-independent phosphorylation of Stat1, Stat5, and Erk (PMID: 21393331, PMID: 31892268), transformation of cultured cells, and tumor formation in mouse models (PMID: 21393331). | |
| JAK1 | V658I | missense | gain of function | JAK1 V658I lies within the protein kinase domain 1 of the Jak1 protein (UniProt.org). V658I results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk, and is transforming in cell culture (PMID: 21393331). | |
| JAK1 | V658L | missense | gain of function | JAK1 V658L lies within the protein kinase domain 1 of the Jak1 protein (UniProt.org). V658L results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk, and is transforming in cell culture (PMID: 21393331, PMID: 20868368). | |
| JAK1 | Y1035C | missense | gain of function | JAK1 Y1035C lies within the protein kinase domain 2 of the Jak1 protein (UniProt.org). Y1035C results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk, and is transforming in cell culture (PMID: 21393331, PMID: 20868368). | |
| JAK1 | Y652H | missense | gain of function | JAK1 Y652H lies within the protein kinase domain 1 of the Jak1 protein (UniProt.org). Y652H results in constitutive Jak1 activation, increased phosphorylation of Stat5 and Erk, and is transforming in cell culture (PMID: 21393331, PMID: 21551237). | |
| 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 |
|---|---|---|---|---|---|---|---|
| JAK1 S646F | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 S646F were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 F635V | Advanced Solid Tumor | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 F635V were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 Y1035C | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 Y1035C were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 V658F | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing JAK1 V658F were sensitive to ATP-competitive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 L910Q | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 L910Q were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 D895H | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 D895H were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 P815S | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 P815S were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 F958V | cancer | resistant | Ruxolitinib | Preclinical | Actionable | In a preclinical study, cells harboring JAK1 F958V displayed resistance to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 T901R | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 T901R were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 F958S | cancer | resistant | Ruxolitinib | Preclinical | Actionable | In a preclinical study, cells harboring JAK1 F958S displayed resistance to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 A723D | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 A723D were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 Y652H | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 Y652H were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 F734L | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 F734L were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 L783F | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 L783F were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 F958C | cancer | resistant | Ruxolitinib | Preclinical | Actionable | In a preclinical study, cells harboring JAK1 F958C displayed resistance to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 V658I | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 V658I were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 P960S | cancer | resistant | Ruxolitinib | Preclinical | Actionable | In a preclinical study, cells harboring JAK1 P960S displayed resistance to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 P960T | cancer | resistant | Ruxolitinib | Preclinical | Actionable | In a preclinical study, cells harboring JAK1 P960T 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 |
| JAK1 F958L | cancer | resistant | Ruxolitinib | Preclinical | Actionable | In a preclinical study, cells harboring JAK1 F958L displayed resistance to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 S1043I | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 S1043I were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 S703I | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 S703I were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 V658F JAK1 F958C | cancer | resistant | Ruxolitinib | Preclinical | Actionable | In a preclinical study, cells harboring the JAK1 V658F/F958C double mutation 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 |
| JAK1 V658L | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 V658L were sensitive to ATP-competetive JAK (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 R724S | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 R724S were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 K1026E | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 K1026E were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |
| JAK1 E897K | cancer | sensitive | Ruxolitinib | Preclinical | Actionable | In a preclinical study, transformed cells harboring JAK1 E897K were sensitive to ATP-competetive JAK inhibitors, such as Jakafi (Ruxolitinib) (PMID: 21393331). | 21393331 |