Molecule Information

General Information of the Molecule (ID: Mol00102)

• Name: Tyrosine-protein kinase JAK2 (JAK3) ,Homo sapiens
• Synonyms: Janus kinase 2; JAK-2
• Molecule Type: Protein
• Gene Name: JAK2
• Gene ID: 3717
• Location: chr9:4984390-5129948[+]
• Sequence:
  MGMACLTMTEMEGTSTSSIYQNGDISGNANSMKQIDPVLQVYLYHSLGKSEADYLTFPSG
  EYVAEEICIAASKACGITPVYHNMFALMSETERIWYPPNHVFHIDESTRHNVLYRIRFYF
  PRWYCSGSNRAYRHGISRGAEAPLLDDFVMSYLFAQWRHDFVHGWIKVPVTHETQEECLG
  MAVLDMMRIAKENDQTPLAIYNSISYKTFLPKCIRAKIQDYHILTRKRIRYRFRRFIQQF
  SQCKATARNLKLKYLINLETLQSAFYTEKFEVKEPGSGPSGEEIFATIIITGNGGIQWSR
  GKHKESETLTEQDLQLYCDFPNIIDVSIKQANQEGSNESRVVTIHKQDGKNLEIELSSLR
  EALSFVSLIDGYYRLTADAHHYLCKEVAPPAVLENIQSNCHGPISMDFAISKLKKAGNQT
  GLYVLRCSPKDFNKYFLTFAVERENVIEYKHCLITKNENEEYNLSGTKKNFSSLKDLLNC
  YQMETVRSDNIIFQFTKCCPPKPKDKSNLLVFRTNGVSDVPTSPTLQRPTHMNQMVFHKI
  RNEDLIFNESLGQGTFTKIFKGVRREVGDYGQLHETEVLLKVLDKAHRNYSESFFEAASM
  MSKLSHKHLVLNYGVCVCGDENILVQEFVKFGSLDTYLKKNKNCINILWKLEVAKQLAWA
  MHFLEENTLIHGNVCAKNILLIREEDRKTGNPPFIKLSDPGISITVLPKDILQERIPWVP
  PECIENPKNLNLATDKWSFGTTLWEICSGGDKPLSALDSQRKLQFYEDRHQLPAPKWAEL
  ANLINNCMDYEPDFRPSFRAIIRDLNSLFTPDYELLTENDMLPNMRIGALGFSGAFEDRD
  PTQFEERHLKFLQQLGKGNFGSVEMCRYDPLQDNTGEVVAVKKLQHSTEEHLRDFEREIE
  ILKSLQHDNIVKYKGVCYSAGRRNLKLIMEYLPYGSLRDYLQKHKERIDHIKLLQYTSQI
  CKGMEYLGTKRYIHRDLATRNILVENENRVKIGDFGLTKVLPQDKEYYKVKEPGESPIFW
  YAPESLTESKFSVASDVWSFGVVLYELFTYIEKSKSPPAEFMRMIGNDKQGQMIVFHLIE
  LLKNNGRLPRPDGCPDEIYMIMTECWNNNVNQRPSFRDLALRVDQIRDNMAG
• Function: Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. Part of a signaling cascade that is activated by increased cellular retinol and that leads to the activation of STAT5 (STAT5A or STAT5B). In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin.
• Uniprot ID: JAK2_HUMAN
• Ensembl ID: ENSG00000096968
• HGNC ID: HGNC:6192

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Cetuximab

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Head and neck squamous cell carcinoma [1]

• Sensitive Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Sensitive Drug: Cetuximab
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT3 signaling pathway; Inhibition; hsa04030
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR204 inhibits angiogenesis and promotes sensitivity to cetuximab in head and neck squamous cell carcinoma cells by blocking JAk2-STAT3 signaling.

Danazol

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Primary myelofibrosis [2]

• Sensitive Disease: Primary myelofibrosis [ICD-11: 2A20.2]
• Sensitive Drug: Danazol
• Molecule Alteration: Function; Inhibition
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: In non-transplant candidates, conventional treatment for anemia includes androgens, prednisone, thalidomide, and danazol; for symptomatic splenomegaly, hydroxyurea and ruxolitinib; and for constitutional symptoms, ruxolitinib. Fedratinib, another JAK2 inhibitor, has now been FDA-approved for use in ruxolitinib failures.

Fedratinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Hematologic Cancer [3]

• Resistant Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Resistant Drug: Fedratinib
• Molecule Alteration: Missense mutation; p.R867Q (c.2600G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 cell proliferation assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Primary myelofibrosis [2]

• Sensitive Disease: Primary myelofibrosis [ICD-11: 2A20.2]
• Sensitive Drug: Fedratinib
• Molecule Alteration: Function; Inhibition
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: In non-transplant candidates, conventional treatment for anemia includes androgens, prednisone, thalidomide, and danazol; for symptomatic splenomegaly, hydroxyurea and ruxolitinib; and for constitutional symptoms, ruxolitinib. Fedratinib, another JAK2 inhibitor, has now been FDA-approved for use in ruxolitinib failures.

Disease Class: Chronic myeloid leukemia [4]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Sensitive Drug: Fedratinib
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The missense mutation p.V617F (c.1849G>T) in gene JAK2 cause the sensitivity of Fedratinib by aberration of the drug's therapeutic target

Ruxolitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Polycythaemia vera [5]

• Resistant Disease: Polycythaemia vera [ICD-11: 2A20.4]
• Resistant Drug: Ruxolitinib
• Molecule Alteration: Missense mutation; p.V617F
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: JAK2 mutation confers resistance to Ruxolitinib.

Disease Class: Acute lymphocytic leukemia [6]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Resistant Drug: Ruxolitinib
• Molecule Alteration: Missense mutation; p.R938Q (c.2813G>A)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: Mutations within the kinase domain of JAK2 are associated with resistance to type I JAK inhibitors.

Disease Class: Hematologic Cancer [3]

• Resistant Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Resistant Drug: Ruxolitinib
• Molecule Alteration: Missense mutation; p.R867Q (c.2600G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 cell proliferation assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Primary myelofibrosis [2]

• Sensitive Disease: Primary myelofibrosis [ICD-11: 2A20.2]
• Sensitive Drug: Ruxolitinib
• Molecule Alteration: Function; Inhibition
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: In non-transplant candidates, conventional treatment for anemia includes androgens, prednisone, thalidomide, and danazol; for symptomatic splenomegaly, hydroxyurea and ruxolitinib; and for constitutional symptoms, ruxolitinib. Fedratinib, another JAK2 inhibitor, has now been FDA-approved for use in ruxolitinib failures.

Disease Class: Acute myeloid leukemia [7]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Ruxolitinib
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Mechanism Description: The missense mutation p.V617F (c.1849G>T) in gene JAK2 cause the sensitivity of Ruxolitinib by aberration of the drug's therapeutic target

Disease Class: Acute lymphocytic leukemia [8]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Sensitive Drug: Ruxolitinib
• Molecule Alteration: Missense mutation; p.R683G (c.2047A>G)
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute lymphocytic leukemia [9]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Sensitive Drug: Ruxolitinib
• Molecule Alteration: Missense mutation; p.F694L (c.2080T>C)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT3 signaling pathway; Inhibition; hsa04030

Clinical Trial Drug(s) 6 drug(s) in total

Momelotinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Hematologic Cancer [3]

• Resistant Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Resistant Drug: Momelotinib
• Molecule Alteration: Missense mutation; p.R867Q (c.2600G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 cell proliferation assay

Ropeginterferon alfa-2b

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [10]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Sensitive Drug: Ropeginterferon alfa-2b
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: UKE-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0104
• Experiment for Drug Resistance: Trypan blue staining assay

Disease Class: Myeloproliferative neoplasm [10]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: Ropeginterferon alfa-2b
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: UKE-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0104
• Experiment for Drug Resistance: Trypan blue staining assay

AUY922

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hematologic Cancer [3]

• Resistant Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Resistant Drug: AUY922
• Molecule Alteration: Missense mutation; p.R867Q (c.2600G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 cell proliferation assay

BMS-911543

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Myeloproliferative neoplasm [11]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: BMS-911543
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: [3H] thymidine incorporation assay
• Mechanism Description: The missense mutation p.V617F (c.1849G>T) in gene JAK2 cause the sensitivity of BMS-911543 by aberration of the drug's therapeutic target

Disease Class: Essential thrombocythemia [11]

• Sensitive Disease: Essential thrombocythemia [ICD-11: 3B63.Z]
• Sensitive Drug: BMS-911543
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: [3H] thymidine incorporation assay
• Mechanism Description: The missense mutation p.V617F (c.1849G>T) in gene JAK2 cause the sensitivity of BMS-911543 by aberration of the drug's therapeutic target

Disease Class: Hematologic Cancer [11]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: BMS-911543
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: [3H] thymidine incorporation assay
• Mechanism Description: The missense mutation p.V617F (c.1849G>T) in gene JAK2 cause the sensitivity of BMS-911543 by aberration of the drug's therapeutic target

Gandotinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Myeloproliferative neoplasm [12]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: Gandotinib
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Identified from the Human Clinical Data

NS-018

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Hematologic Cancer [13]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: NS-018
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Sf9 cells; Ovary; Homo sapiens (Human); CVCL_0549
• Experiment for Molecule Alteration: Colony formation assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.V617F (c.1849G>T) in gene JAK2 cause the sensitivity of NS-018 by aberration of the drug's therapeutic target

Preclinical Drug(s) 7 drug(s) in total

A-1155463

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [14]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: A-1155463
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SCLC cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: NHL cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: SCID and SCID-bg mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony formation assay

AZD1208/Ruxolitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Metastatic bone cancer [15]

• Sensitive Disease: Metastatic bone cancer [ICD-11: 2E03.0]
• Sensitive Drug: AZD1208/Ruxolitinib
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: UKE-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0104
• In Vitro Model: UKE-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0104
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vitro Model: JAK2-V617F cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: Western blotting analysis; Microarray gene expression analysis; Crystallization and structure determination assay
• Experiment for Drug Resistance: MTS assay; Colony formation assay

Disease Class: Metastatic bone cancer [15]

• Sensitive Disease: Metastatic bone cancer [ICD-11: 2E03.0]
• Sensitive Drug: AZD1208/Ruxolitinib
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: UKE-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0104
• In Vitro Model: UKE-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0104
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vitro Model: JAK2-V617F cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: Western blotting analysis; Microarray gene expression analysis; Crystallization and structure determination assay
• Experiment for Drug Resistance: MTS assay; Colony formation assay

CHZ868

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Metastatic bone cancer [16]

• Sensitive Disease: Metastatic bone cancer [ICD-11: 2E03.0]
• Sensitive Drug: CHZ868
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: W515L cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vivo Model: CD45.2 Jak2V617F mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell viability luminescent assay

Pictilisib/Ruxolitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [17]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Pictilisib/Ruxolitinib
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: JAK2 mutant Ba/F3 tumour mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony assay

Ruxolitinib/SGI-1776

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Metastatic bone cancer [15]

• Sensitive Disease: Metastatic bone cancer [ICD-11: 2E03.0]
• Sensitive Drug: Ruxolitinib/SGI-1776
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: UKE-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0104
• In Vitro Model: UKE-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0104
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vitro Model: JAK2-V617F cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: Western blotting analysis; Microarray gene expression analysis; Crystallization and structure determination assay
• Experiment for Drug Resistance: MTS assay; Colony formation assay

Ruxolitinib/ZSTK474

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [17]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Ruxolitinib/ZSTK474
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: JAK2 mutant Ba/F3 tumour mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony assay

SHP099

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hematologic Cancer [18]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: SHP099
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: RAS/ERK signaling pathway; Inhibition; hsa01521
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: NCI-H2228 cells; Lung; Homo sapiens (Human); CVCL_1543
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: KYSE520 cells; Esophagus; Homo sapiens (Human); CVCL_1355
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: Sum52 cells; Pleural effusion; Homo sapiens (Human); CVCL_3425
• In Vitro Model: NCI-H2170 cells; Lung; Homo sapiens (Human); CVCL_1535
• In Vitro Model: NCI-H2170 cells; Lung; Homo sapiens (Human); CVCL_1535
• In Vitro Model: H293 cells; Kidney; Homo sapiens (Human); N.A.
• In Vivo Model: Athymic nude mouse PDX model; Mus musculus
• Experiment for Drug Resistance: CellTitre-Glo assay; Crystal violet staining assay
• Mechanism Description: SHP099 suppresses RAS-ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models.

Investigative Drug(s) 4 drug(s) in total

AZ960

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Hematologic Cancer [3]

• Resistant Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Resistant Drug: AZ960
• Molecule Alteration: Missense mutation; p.R867Q (c.2600G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 cell proliferation assay

GO6976

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [19]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: GO6976
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: Mo7E cells; Peripheral blood; Homo sapiens (Human); CVCL_2106
• In Vitro Model: FDCP1 cells; Bone marrow; Mus musculus (Mouse); CVCL_2039
• In Vitro Model: 32D cells; Bone marrow; Homo sapiens (Human); CVCL_0118
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.V617F (c.1849G>T) in gene JAK2 cause the sensitivity of Go6976 by unusual activation of pro-survival pathway

Peginterferon alfa-2a

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [20]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Sensitive Drug: Peginterferon alfa-2a
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Mechanism Description: The missense mutation p.V617F (c.1849G>T) in gene JAK2 cause the sensitivity of Peginterferon alfa-2a by unusual activation of pro-survival pathway

Pyridone 6

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast adenocarcinoma [21]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Pyridone 6
• Molecule Alteration: Copy number gain; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT/STAT signaling pathway; Inhibition; hsa04630
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: HCC1954 cells; Breast; Homo sapiens (Human); CVCL_1259
• In Vitro Model: MDA-231 cells; Pleural effusion; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-436 cells; Breast; Homo sapiens (Human); CVCL_0623
• In Vitro Model: SUM159PT cells; Breast; Homo sapiens (Human); CVCL_5423/CVCL_5590
• In Vitro Model: HCC38 cells; Breast; Homo sapiens (Human); CVCL_1267
• In Vitro Model: HCC1143 cells; Breast; Homo sapiens (Human); CVCL_1245
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: SRB assay

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Chronic myeloid leukemia [ICD-11: 2A20]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Whole blood
• The Specified Disease: Myelofibrosis
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.29E-03; Fold-change: 1.98E-01; Z-score: 5.31E-01
• The Studied Tissue: Whole blood
• The Specified Disease: Polycythemia vera
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.41E-07; Fold-change: 3.61E-01; Z-score: 1.03E+00

Acute myeloid leukemia [ICD-11: 2A60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Bone marrow
• The Specified Disease: Acute myeloid leukemia
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.46E-10; Fold-change: -4.97E-01; Z-score: -8.17E-01

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.64E-02; Fold-change: 3.95E-02; Z-score: 5.89E-02
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 8.64E-01; Fold-change: -4.74E-02; Z-score: -6.30E-02

ICD Disease Classification 03

Essential thrombocythemia [ICD-11: 3B63]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Whole blood
• The Specified Disease: Essential thrombocythemia
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.90E-02; Fold-change: 5.70E-02; Z-score: 1.54E-01

References

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