Disease Information

General Information of the Disease (ID: DIS00367)

• Name: Hematologic cancer
• ICD: ICD-11: 2B3Z

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 6 drug(s) in total

Avapritinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [1]

• Resistant Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Resistant Drug: Avapritinib
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>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: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vivo Model: Female NCr-nude mouse model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Avapritinib
• Molecule Alteration: Missense mutation; p.D816V (c.2447A>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: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vivo Model: Female NCr-nude mouse model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Fedratinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• 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 blot analysis
• Experiment for Drug Resistance: WST-1 cell proliferation assay

Gilteritinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [1]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Gilteritinib
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>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: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vivo Model: Female NCr-nude mouse model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Gilteritinib
• Molecule Alteration: Missense mutation; p.D816V (c.2447A>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: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vivo Model: Female NCr-nude mouse model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Midostaurin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [1]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Midostaurin
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>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: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vivo Model: Female NCr-nude mouse model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Midostaurin
• Molecule Alteration: Missense mutation; p.D816V (c.2447A>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: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vivo Model: Female NCr-nude mouse model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Ruxolitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• 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 blot analysis
• Experiment for Drug Resistance: WST-1 cell proliferation assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Calreticulin (CALR) [3]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Ruxolitinib
• Molecule Alteration: FS-insertion; p.K385fs*47 (c.1153_1154insTAATT)
• 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 blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Tofacitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

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

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Tofacitinib
• Molecule Alteration: Missense mutation; p.M511I (c.1533G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: Jak3 inhibitors CP-690,550 and NC1153 showed efficacy in reducing viability of Ba/F3 cells transformed with mutant forms of Jak3.

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

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Tofacitinib
• Molecule Alteration: Missense mutation; p.A573V (c.1718C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: Jak3 inhibitors CP-690,550 and NC1153 showed efficacy in reducing viability of Ba/F3 cells transformed with mutant forms of Jak3.

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [5]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Tofacitinib
• Molecule Alteration: Missense mutation; p.H583Y (c.1747C>T)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT/STAT signaling pathway; Inhibition; hsa04630
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• Experiment for Molecule Alteration: Immunohistochemistry assay; Immunoblotting assay
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: A STAT3 inhibitor was active against STAT3 -mutant SNK-6 and YT cells. Novel JAK3 mutations are oncogenic and druggable in NTCL. The JAK3 or STAT3 signal was altered in NTCL, and pathway inhibition might be a therapeutic option for patients with JAK3 - or STAT3 -mutant NTCL.

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [5]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Tofacitinib
• Molecule Alteration: Missense mutation; p.G589D (c.1766G>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT/STAT signaling pathway; Inhibition; hsa04630
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• Experiment for Molecule Alteration: Immunohistochemistry assay; Immunoblotting assay
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: A STAT3 inhibitor was active against STAT3 -mutant SNK-6 and YT cells. Novel JAK3 mutations are oncogenic and druggable in NTCL. The JAK3 or STAT3 signal was altered in NTCL, and pathway inhibition might be a therapeutic option for patients with JAK3 - or STAT3 -mutant NTCL.

Clinical Trial Drug(s) 8 drug(s) in total

Crenolanib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [6]

• Resistant Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Resistant Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.K429E (c.1285A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Whole exome sequencing
• Experiment for Drug Resistance: MTS assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [1]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: SKNO-1-luc cells; Bone marrow; Homo sapiens (Human); CVCL_2196
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: Kasumi-1-luc cells; N.A.; N.A.; N.A.
• In Vivo Model: Female NCr-nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue exclusion assay

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [6]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.Y572C (c.1715A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Whole exome sequencing
• Experiment for Drug Resistance: MTS assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.D816V (c.2447A>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: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vivo Model: Female NCr-nude mouse model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Enasidenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [7]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R172K (c.515G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.93 Å; PDB: 5GIS
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.10 Å; PDB: 5SVN

RMSD: 1.13; TM score: 0.29352; Amino acid change: R172K

• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [7]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R140K (c.418_419delCGinsAA)
• Experimental Note: Identified from the Human Clinical Data

Momelotinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• 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 blot analysis
• Experiment for Drug Resistance: WST-1 cell proliferation assay

AUY922

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• 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 blot 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)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [8]

• 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 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) [8]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• 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

FF-10101

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [9]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: FF-10101
• Molecule Alteration: Missense mutation; p.D816V (c.2447A>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vivo Model: NOD/SCID mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony formation assay

NS-018

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [10]

• 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

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Thrombopoietin receptor (TPOR) [10]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: NS-018
• Molecule Alteration: Missense mutation; p.W515L (c.1544G>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.W515L (c.1544G>T) in gene MPL cause the sensitivity of NS-018 by unusual activation of pro-survival pathway

LY3009120

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [11]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: LY3009120
• Molecule Alteration: Missense mutation; p.K601N (c.1803A>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: OV-90 cells; Ascites; Homo sapiens (Human); CVCL_3768
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vivo Model: NIH nude rat xenograft model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony transformation assay; Cell-cycle analysis; BrdUrd incorporation assay

Preclinical Drug(s) 5 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) [12]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• 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

Crenolanib/Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [6]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Crenolanib/Trametinib
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Whole exome sequencing
• Experiment for Drug Resistance: MTS assay

E7107

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Splicing factor 3B subunit 1 (SF3B1) [13]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: E7107
• Molecule Alteration: Missense mutation; p.K700E (c.2098A>G)
• Experimental Note: Identified from the Human Clinical Data

II-B08

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) [14]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: II-B08
• Molecule Alteration: Missense mutation; p.E76K (c.226G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.70 Å; PDB: 5EHR
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.62 Å; PDB: 6CRF

RMSD: 3.04; TM score: 0.6516; Amino acid change: E76K

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: 3H-thymidine incorporation assay
• Mechanism Description: The missense mutation p.E76K (c.226G>A) in gene PTPN11 cause the sensitivity of II-B08 by unusual activation of pro-survival pathway

SHP099

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [15]

• 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) 2 drug(s) in total

AZ960

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• 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 blot analysis
• Experiment for Drug Resistance: WST-1 cell proliferation assay

G-749

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [16]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: G-749
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: KG1a cells; Pleural effusion; Homo sapiens (Human); CVCL_1824
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• Experiment for Molecule Alteration: Kinase inhibition assessment assay
• Experiment for Drug Resistance: Fluorometric microculture cytotoxicity assay
• Mechanism Description: The missense mutation p.D835Y (c.2503G>T) in gene FLT3 cause the sensitivity of G-749 by aberration of the drug's therapeutic target

References

• Ref 1: Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU-285 on oncogenic mutants of KIT, CBL and FLT3 in haematological malignanciesBr J Haematol. 2019 Nov;187(4):488-501. doi: 10.1111/bjh.16092. Epub 2019 Jul 15.
• Ref 2: Germ-line JAK2 mutations in the kinase domain are responsible for hereditary thrombocytosis and are resistant to JAK2 and HSP90 inhibitorsBlood. 2014 Feb 27;123(9):1372-83. doi: 10.1182/blood-2013-05-504555. Epub 2014 Jan 7.
• Ref 3: Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutantsBlood. 2016 Mar 10;127(10):1325-35. doi: 10.1182/blood-2015-11-681932. Epub 2015 Dec 14.
• Ref 4: Transforming Mutations of Jak3 (A573V and M511I) Show Differential Sensitivity to Selective Jak3 InhibitorsClin Cancer Drugs. 2016;3(2):131-137. doi: 10.2174/2212697X03666160610085943.
• Ref 5: Novel JAK3-Activating Mutations in Extranodal NK/T-Cell Lymphoma, Nasal TypeAm J Pathol. 2017 May;187(5):980-986. doi: 10.1016/j.ajpath.2017.01.004. Epub 2017 Mar 9.
• Ref 6: Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanismsNat Commun. 2019 Jan 16;10(1):244. doi: 10.1038/s41467-018-08263-x.
• Ref 7: Abstract CT103: Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-0280.
• Ref 8: 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 9: A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutationsBlood. 2018 Jan 25;131(4):426-438. doi: 10.1182/blood-2017-05-786657. Epub 2017 Nov 29.
• Ref 10: Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasmsBlood Cancer J. 2011 Jul;1(7):e29. doi: 10.1038/bcj.2011.29. Epub 2011 Jul 22.
• Ref 11: Oncogenic BRAF Deletions That Function as Homodimers and Are Sensitive to Inhibition by RAF Dimer Inhibitor LY3009120Cancer Discov. 2016 Mar;6(3):300-15. doi: 10.1158/2159-8290.CD-15-0896. Epub 2016 Jan 5.
• Ref 12: 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 13: Physiologic Expression of Sf3b1(K700E) Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome ModulationCancer Cell. 2016 Sep 12;30(3):404-417. doi: 10.1016/j.ccell.2016.08.006.
• Ref 14: Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)J Med Chem. 2010 Mar 25;53(6):2482-93. doi: 10.1021/jm901645u.
• Ref 15: Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinasesNature. 2016 Jul 7;535(7610):148-52. doi: 10.1038/nature18621. Epub 2016 Jun 29.
• Ref 16: The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemiaBlood Cancer J. 2012 Aug 3;2(8):e81. doi: 10.1038/bcj.2012.28.