Disease Information

General Information of the Disease (ID: DIS00190)

• Name: Myeloproliferative neoplasm
• ICD: ICD-11: 2A22

Type(s) of Resistant Mechanism of This Disease

  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) 3 drug(s) in total

Fedratinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Resistant Drug: Fedratinib
• Molecule Alteration: Mutation; V617F+L902Q+E1028K
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. These results suggest that fedratinib might be effective in the suppression of ATP site mutations generated by ruxolitinib due to its ability to bind additional substrate binding sites.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Resistant Drug: Fedratinib
• Molecule Alteration: Mutation; V617F+L902Q+R938E
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. These results suggest that fedratinib might be effective in the suppression of ATP site mutations generated by ruxolitinib due to its ability to bind additional substrate binding sites.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Resistant Drug: Fedratinib
• Molecule Alteration: Mutation; V617F+L902Q+R947Q
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. These results suggest that fedratinib might be effective in the suppression of ATP site mutations generated by ruxolitinib due to its ability to bind additional substrate binding sites.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Resistant Drug: Fedratinib
• Molecule Alteration: Mutation; V617F+Y931C
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. These results suggest that fedratinib might be effective in the suppression of ATP site mutations generated by ruxolitinib due to its ability to bind additional substrate binding sites.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: Fedratinib
• Molecule Alteration: Mutation; V617F+L902Q+E1028K
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. These results suggest that fedratinib might be effective in the suppression of ATP site mutations generated by ruxolitinib due to its ability to bind additional substrate binding sites.

Pomalidomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein cereblon (CRBN) [2]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Resistant Drug: Pomalidomide
• Molecule Alteration: Nonsense; p.Q100* (c.298C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The nonsense p.Q100* (c.298C>T) in gene CRBN cause the resistance of Pomalidomide by unusual activation of pro-survival pathway.

Key Molecule: Protein cereblon (CRBN) [2]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Resistant Drug: Pomalidomide
• Molecule Alteration: Missense mutation; p.R283K (c.848G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.R283K (c.848G>A) in gene CRBN cause the resistance of Pomalidomide by unusual activation of pro-survival pathway

Ruxolitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Resistant Drug: Ruxolitinib
• Molecule Alteration: Mutation; V617F+L902Q
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Resistant Drug: Ruxolitinib
• Molecule Alteration: Mutation; V617F+L902Q+R938E
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Resistant Drug: Ruxolitinib
• Molecule Alteration: Mutation; V617F+L902Q+R947Q
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Resistant Drug: Ruxolitinib
• Molecule Alteration: Mutation; V617F+L983F
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Resistant Drug: Ruxolitinib
• Molecule Alteration: Mutation; V617F+L983F+Q959H
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Resistant Drug: Ruxolitinib
• Molecule Alteration: Mutation; V617F+Y931C
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles.

Clinical Trial Drug(s) 5 drug(s) in total

Ropeginterferon alfa-2b

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [3]

• 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

BMS-911543

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [4]

• 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 blot 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

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Thrombopoietin receptor (TPOR) [4]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: BMS-911543
• Molecule Alteration: Missense mutation; p.W515L (c.1544G>T)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: [3H] thymidine incorporation assay
• Mechanism Description: The missense mutation p.W515L (c.1544G>T) in gene MPL cause the sensitivity of BMS-911543 by unusual activation of pro-survival pathway

DEBIO-1347

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [5]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: DEBIO-1347
• Molecule Alteration: Missense mutation; p.K650E (c.1948A>G)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.53 Å; PDB: 6LVM
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.34 Å; PDB: 4K33

RMSD: 1.24; TM score: 0.96738; Amino acid change: K650E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; N.A.; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [5]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: DEBIO-1347
• Molecule Alteration: Missense mutation; p.Y373C (c.1118A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; N.A.; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [5]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: DEBIO-1347
• Molecule Alteration: Missense mutation; p.F386L (c.1156T>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; N.A.; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK-8 assay

Gandotinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [6]

• 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

Tanespimycin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: Tanespimycin
• Molecule Alteration: Mutation; V617F+L902Q
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: These results indicate that these mutants are dependent on the HSP90 for their folding. To know that downregulation of JAK2 protein leads to the decrease of cell proliferation, we performed biochemical analysis on these mutant JAK2 cells and found that ruxolitinib-resistant variants are sensitive towards 17-AAG and treatment of the cells with 17-AAG leads to the downregulation of JAK2 protein and decrease of STAT5 activation. This study shows that HSP90 inhibitors are potent against ruxolitinib-resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: Tanespimycin
• Molecule Alteration: Mutation; V617F+L902Q+E1028K
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: These results indicate that these mutants are dependent on the HSP90 for their folding. To know that downregulation of JAK2 protein leads to the decrease of cell proliferation, we performed biochemical analysis on these mutant JAK2 cells and found that ruxolitinib-resistant variants are sensitive towards 17-AAG and treatment of the cells with 17-AAG leads to the downregulation of JAK2 protein and decrease of STAT5 activation. This study shows that HSP90 inhibitors are potent against ruxolitinib-resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: Tanespimycin
• Molecule Alteration: Mutation; V617F+L902Q+R938E
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: These results indicate that these mutants are dependent on the HSP90 for their folding. To know that downregulation of JAK2 protein leads to the decrease of cell proliferation, we performed biochemical analysis on these mutant JAK2 cells and found that ruxolitinib-resistant variants are sensitive towards 17-AAG and treatment of the cells with 17-AAG leads to the downregulation of JAK2 protein and decrease of STAT5 activation. This study shows that HSP90 inhibitors are potent against ruxolitinib-resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: Tanespimycin
• Molecule Alteration: Mutation; V617F+L902Q+R947Q
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: These results indicate that these mutants are dependent on the HSP90 for their folding. To know that downregulation of JAK2 protein leads to the decrease of cell proliferation, we performed biochemical analysis on these mutant JAK2 cells and found that ruxolitinib-resistant variants are sensitive towards 17-AAG and treatment of the cells with 17-AAG leads to the downregulation of JAK2 protein and decrease of STAT5 activation. This study shows that HSP90 inhibitors are potent against ruxolitinib-resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: Tanespimycin
• Molecule Alteration: Mutation; V617F+L983F
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: These results indicate that these mutants are dependent on the HSP90 for their folding. To know that downregulation of JAK2 protein leads to the decrease of cell proliferation, we performed biochemical analysis on these mutant JAK2 cells and found that ruxolitinib-resistant variants are sensitive towards 17-AAG and treatment of the cells with 17-AAG leads to the downregulation of JAK2 protein and decrease of STAT5 activation. This study shows that HSP90 inhibitors are potent against ruxolitinib-resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: Tanespimycin
• Molecule Alteration: Mutation; V617F+L983F+Q959H
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: These results indicate that these mutants are dependent on the HSP90 for their folding. To know that downregulation of JAK2 protein leads to the decrease of cell proliferation, we performed biochemical analysis on these mutant JAK2 cells and found that ruxolitinib-resistant variants are sensitive towards 17-AAG and treatment of the cells with 17-AAG leads to the downregulation of JAK2 protein and decrease of STAT5 activation. This study shows that HSP90 inhibitors are potent against ruxolitinib-resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: Tanespimycin
• Molecule Alteration: Mutation; V617F+Y931C
• 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: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: These results indicate that these mutants are dependent on the HSP90 for their folding. To know that downregulation of JAK2 protein leads to the decrease of cell proliferation, we performed biochemical analysis on these mutant JAK2 cells and found that ruxolitinib-resistant variants are sensitive towards 17-AAG and treatment of the cells with 17-AAG leads to the downregulation of JAK2 protein and decrease of STAT5 activation. This study shows that HSP90 inhibitors are potent against ruxolitinib-resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors.

Preclinical Drug(s) 3 drug(s) in total

CHZ868

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Thrombopoietin receptor (TPOR) [7]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: CHZ868
• Molecule Alteration: Missense mutation; p.W515L (c.1544G>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 blot analysis
• Experiment for Drug Resistance: Cell viability luminescent assay

MK2206

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Thrombopoietin receptor (TPOR) [8]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: MK2206
• Molecule Alteration: Missense mutation; p.W515L (c.1544G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vivo Model: Balb/c donor mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: Trypan blue staining assay
• Mechanism Description: The missense mutation p.W515L (c.1544G>T) in gene MPL cause the sensitivity of MK2206 by unusual activation of pro-survival pathway

SU5402

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [9]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: SU5402
• Molecule Alteration: Missense mutation; p.K650E (c.1948A>G)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.53 Å; PDB: 6LVM
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.34 Å; PDB: 4K33

RMSD: 1.24; TM score: 0.96738; Amino acid change: K650E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Blood vessel; N.A.
• Experiment for Molecule Alteration: Mass spectrum assay
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: The missense mutation p.K650E (c.1948A>G) in gene FGFR3 cause the sensitivity of SU5402 by aberration of the drug's therapeutic target

Investigative Drug(s) 1 drug(s) in total

Pyridone 6

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: E3 ubiquitin-protein ligase CBL (CBL) [10]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: Pyridone 6
• Molecule Alteration: Missense mutation; p.C384R (c.1150T>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The missense mutation p.C384R (c.1150T>C) in gene CBL cause the sensitivity of JAK inhibitors by unusual activation of pro-survival pathway

Key Molecule: Thrombopoietin receptor (TPOR) [11]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: Pyridone 6
• Molecule Alteration: Missense mutation; p.W515F (c.1544_1545delGGinsTT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• In Vivo Model: Balb/C donor mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: In vitro colony-forming assay
• Mechanism Description: The missense mutation p.W515F (c.1544_1545delGGinsTT) in gene MPL cause the sensitivity of JAK inhibitors by unusual activation of pro-survival pathway

References

• Ref 1: Type II mode of JAK2 inhibition and destabilization are potential therapeutic approaches against the ruxolitinib resistance driven myeloproliferative neoplasms. Front Oncol. 2024 Jul 18;14:1430833.
• Ref 2: Extramedullary myeloma whole genome sequencing reveals novel mutations in Cereblon, proteasome subunit G2 and the glucocorticoid receptor in multi drug resistant disease. Br J Haematol. 2013 Jun;161(5):748-51. doi: 10.1111/bjh.12291. Epub 2013 Mar 11.
• Ref 3: Ropeginterferon alpha-2b targets JAK2V617F-positive polycythemia vera cells in vitro and in vivoBlood Cancer J. 2018 Oct 4;8(10):94. doi: 10.1038/s41408-018-0133-0.
• Ref 4: Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2Leukemia. 2012 Feb;26(2):280-8. doi: 10.1038/leu.2011.292. Epub 2011 Oct 21.
• Ref 5: The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitorMol Cancer Ther. 2014 Nov;13(11):2547-58. doi: 10.1158/1535-7163.MCT-14-0248. Epub 2014 Aug 28.
• Ref 6: A phase 1 study of the Janus kinase 2 (JAK2)(V617F) inhibitor, gandotinib (LY2784544), in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemiaLeuk Res. 2017 Oct;61:89-95. doi: 10.1016/j.leukres.2017.08.010. Epub 2017 Aug 31.
• Ref 7: CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative NeoplasmsCancer Cell. 2015 Jul 13;28(1):15-28. doi: 10.1016/j.ccell.2015.06.006.
• Ref 8: AKT is a therapeutic target in myeloproliferative neoplasmsLeukemia. 2013 Sep;27(9):1882-90. doi: 10.1038/leu.2013.167. Epub 2013 Jun 10.
• Ref 9: Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric propertiesCancer Cell. 2013 Apr 15;23(4):477-88. doi: 10.1016/j.ccr.2013.02.019.
• Ref 10: CBL linker region and RING finger mutations lead to enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling via elevated levels of JAK2 and LYNJ Biol Chem. 2013 Jul 5;288(27):19459-70. doi: 10.1074/jbc.M113.475087. Epub 2013 May 21.
• Ref 11: MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasiaPLoS Med. 2006 Jul;3(7):e270. doi: 10.1371/journal.pmed.0030270.