Molecule Information

General Information of the Molecule (ID: Mol00375)

• Name: Receptor-type tyrosine-protein kinase FLT3 (FLT3) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: FLT3
• Gene ID: 2322
• Location: chr13:28003274-28100592[-]
• Sequence:
  MPALARDGGQLPLLVVFSAMIFGTITNQDLPVIKCVLINHKNNDSSVGKSSSYPMVSESP
  EDLGCALRPQSSGTVYEAAAVEVDVSASITLQVLVDAPGNISCLWVFKHSSLNCQPHFDL
  QNRGVVSMVILKMTETQAGEYLLFIQSEATNYTILFTVSIRNTLLYTLRRPYFRKMENQD
  ALVCISESVPEPIVEWVLCDSQGESCKEESPAVVKKEEKVLHELFGTDIRCCARNELGRE
  CTRLFTIDLNQTPQTTLPQLFLKVGEPLWIRCKAVHVNHGFGLTWELENKALEEGNYFEM
  STYSTNRTMIRILFAFVSSVARNDTGYYTCSSSKHPSQSALVTIVEKGFINATNSSEDYE
  IDQYEEFCFSVRFKAYPQIRCTWTFSRKSFPCEQKGLDNGYSISKFCNHKHQPGEYIFHA
  ENDDAQFTKMFTLNIRRKPQVLAEASASQASCFSDGYPLPSWTWKKCSDKSPNCTEEITE
  GVWNRKANRKVFGQWVSSSTLNMSEAIKGFLVKCCAYNSLGTSCETILLNSPGPFPFIQD
  NISFYATIGVCLLFIVVLTLLICHKYKKQFRYESQLQMVQVTGSSDNEYFYVDFREYEYD
  LKWEFPRENLEFGKVLGSGAFGKVMNATAYGISKTGVSIQVAVKMLKEKADSSEREALMS
  ELKMMTQLGSHENIVNLLGACTLSGPIYLIFEYCCYGDLLNYLRSKREKFHRTWTEIFKE
  HNFSFYPTFQSHPNSSMPGSREVQIHPDSDQISGLHGNSFHSEDEIEYENQKRLEEEEDL
  NVLTFEDLLCFAYQVAKGMEFLEFKSCVHRDLAARNVLVTHGKVVKICDFGLARDIMSDS
  NYVVRGNARLPVKWMAPESLFEGIYTIKSDVWSYGILLWEIFSLGVNPYPGIPVDANFYK
  LIQNGFKMDQPFYATEEIYIIMQSCWAFDSRKRPSFPNLTSFLGCQLADAEEAMYQNVDG
  RVSECPHTYQNRRPFSREMDLGLLSPQAQVEDS
• Function: Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways.
• Uniprot ID: FLT3_HUMAN
• Ensembl ID: ENSG00000122025
• HGNC ID: HGNC:3765

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

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

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

Avapritinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hematologic Cancer [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

Gilteritinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Hematologic Cancer [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

Lestaurtinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [2]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Lestaurtinib
• Molecule Alteration: Missense mutation; p.D835E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Mechanism Description: Among the mutational patterns underlying relapse, the authors detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TkD mutations) and the increased resistance to apoptosis (hyperactivation of TYk2). Moreover, FLT3/TkD and ITD being subclonal mutations is one of the plausible explanations of unsatisfying results of FLT3 inhibitors, along with many others concerning inadequate in vivo inhibition of the target, development of secondary pharmacokinetic or pharmacodynamic resistance, and influence of FLT3-mutant allelic burden.

Disease Class: Acute myeloid leukemia [2]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Lestaurtinib
• Molecule Alteration: Chromosome variation; FLT3/ITD (Internal tandem duplication )
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Mechanism Description: Among the mutational patterns underlying relapse, the authors detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TkD mutations) and the increased resistance to apoptosis (hyperactivation of TYk2). Moreover, FLT3/TkD and ITD being subclonal mutations is one of the plausible explanations of unsatisfying results of FLT3 inhibitors, along with many others concerning inadequate in vivo inhibition of the target, development of secondary pharmacokinetic or pharmacodynamic resistance, and influence of FLT3-mutant allelic burden.

Midostaurin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Midostaurin
• Molecule Alteration: Missense mutation; p.S451F (c.1352C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.S451F (c.1352C>T) in gene FLT3 cause the resistance of Midostaurin by unusual activation of pro-survival pathway

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Hematologic Cancer [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

Disease Class: Solid tumour/cancer [4]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Midostaurin
• Molecule Alteration: IF-deletion; p.I836delI (c.2508_2510delCAT)
• 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: Immunoblotting analysis
• Mechanism Description: The if-deletion p.I836delI (c.2508_2510delCAT) in gene FLT3 cause the sensitivity of Midostaurin by aberration of the drug's therapeutic target.

Disease Class: Acute myeloid leukemia [5]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Midostaurin
• Molecule Alteration: Missense mutation; p.Y842C (c.2525A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.Y842C (c.2525A>G) in gene FLT3 cause the sensitivity of Midostaurin by aberration of the drug's therapeutic target

Disease Class: Acute myeloid leukemia [6]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Midostaurin
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Mechanism Description: The missense mutation p.D835Y (c.2503G>T) in gene FLT3 cause the sensitivity of Midostaurin by aberration of the drug's therapeutic target

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Midostaurin
• Molecule Alteration: Missense mutation; p.Y572C (c.1715A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.Y572C (c.1715A>G) in gene FLT3 cause the sensitivity of Midostaurin by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Midostaurin
• Molecule Alteration: Missense mutation; p.V592G (c.1775T>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.V592G (c.1775T>G) in gene FLT3 cause the sensitivity of Midostaurin by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Midostaurin
• Molecule Alteration: Missense mutation; p.R834Q (c.2501G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.R834Q (c.2501G>A) in gene FLT3 cause the sensitivity of Midostaurin by unusual activation of pro-survival pathway

Pexidartinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Pexidartinib
• Molecule Alteration: Missense mutation; p.D835Y
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The pexidartinib IC50 values of cells with D835Y mutation was 206, the pexidartinib IC50 value of cells without mutation was 1.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Pexidartinib
• Molecule Alteration: Missense mutation; p.D835V
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The pexidartinib IC50 values of cells with D835V mutation was 320, the pexidartinib IC50 value of cells without mutation was 1.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Pexidartinib
• Molecule Alteration: Missense mutation; p.D835I
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The pexidartinib IC50 values of cells with D835I mutation was 1937, the pexidartinib IC50 value of cells without mutation was 1.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Pexidartinib
• Molecule Alteration: Missense mutation; p.D835F
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The pexidartinib IC50 values of cells with D835F mutation was 415, the pexidartinib IC50 value of cells without mutation was 1.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Pexidartinib
• Molecule Alteration: Frameshift mutation; p.D835Del
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The pexidartinib IC50 values of cells with D835Del mutation was 121, the pexidartinib IC50 value of cells without mutation was 1.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Pexidartinib
• Molecule Alteration: Missense mutation; p.F691L
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The multiple mutations that can confer resistance to quizartinib and pexidartinib. The gatekeeper mutation F691L was the most common mutation in all protocols involving quizartinib; it was rather frequent even with pexidartinib alone.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Pexidartinib
• Molecule Alteration: Missense mutation; p.F691L
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The multiple mutations that can confer resistance to quizartinib and pexidartinib. The gatekeeper mutation F691L was the most common mutation in all protocols involving quizartinib; it was rather frequent even with pexidartinib alone.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Pexidartinib
• Molecule Alteration: Missense mutation; p.F691L
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• Mechanism Description: The gatekeeper mutation F691L confers resistance to specific FLT3 inhibitors such as quizartinib, but pexidartinib is much less resistance to this mutation. Pexidartinib alone is however sensitive to many other resistance mutations.

Disease Class: Solid tumour/cancer [8]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Pexidartinib
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vivo Model: (Nu/Nu) male MV4; 11 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; ATPlite 1step luminescence assay

Disease Class: Solid tumour/cancer [8]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Pexidartinib
• Molecule Alteration: Missense mutation; p.D835V (c.2504A>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vivo Model: (Nu/Nu) male MV4; 11 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; ATPlite 1step luminescence assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Acute myeloid leukemia [7]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Pexidartinib
• Molecule Alteration: Missense mutation+Internal tandem duplication mutation; p.F691L+ FLT3-ITD
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• Mechanism Description: The gatekeeper mutation F691L confers resistance to specific FLT3 inhibitors such as quizartinib, but pexidartinib is much less resistance to this mutation. Pexidartinib alone is however sensitive to many other resistance mutations.

Sorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Acute myeloid leukemia [9]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Sorafenib
• Molecule Alteration: Missense mutation; p.F691
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Southern blot analysis; Spectral karyotyping assay
• Mechanism Description: FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.

Disease Class: Acute myeloid leukemia [9]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Sorafenib
• Molecule Alteration: Missense mutation; p.D835
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Southern blot analysis; Spectral karyotyping assay
• Mechanism Description: FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [10]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Sorafenib
• Molecule Alteration: Missense mutation; p.D835Y
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Aldefluor activity analysis
• Mechanism Description: Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations.

Disease Class: Acute myeloid leukemia [10], [11]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Sorafenib
• Molecule Alteration: Missense mutation; p.D835H
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Aldefluor activity analysis
• Mechanism Description: Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations.

Disease Class: Acute myeloid leukemia [11]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Sorafenib
• Molecule Alteration: Missense mutation; p.F691L
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Deep amplicon sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: In this study, we report the clinical activity of sequential therapy with sorafenib and sunitinib in children with FLT3-ITD-positive AML and the emergence of polyclonal secondary FLT3 TkD mutations during TkI therapy as identified by deep amplicon sequencing.

Sunitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Acute myeloid leukemia [11]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Sunitinib
• Molecule Alteration: Missense mutation; p.D835Y
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Deep amplicon sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: In this study, we report the clinical activity of sequential therapy with sorafenib and sunitinib in children with FLT3-ITD-positive AML and the emergence of polyclonal secondary FLT3 TkD mutations during TkI therapy as identified by deep amplicon sequencing.

Disease Class: Acute myeloid leukemia [9]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Sunitinib
• Molecule Alteration: Missense mutation; p.F691
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Southern blot analysis; Spectral karyotyping assay
• Mechanism Description: FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.

Disease Class: Acute myeloid leukemia [9]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Sunitinib
• Molecule Alteration: Missense mutation; p.D835
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Southern blot analysis; Spectral karyotyping assay
• Mechanism Description: FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.

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

Crenolanib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Hematologic Cancer [12]

• 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)

Disease Class: Hematologic Cancer [12]

• 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

Disease Class: Hematologic Cancer [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.
• In Vivo Model: Female NCr-nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue exclusion assay

Disease Class: Acute myeloid leukemia [13]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Crenolanib
• Molecule Alteration: Missense mutation; p.D835H (c.2503G>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Colony assays; Plasma inhibitory assay

Quizartinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Acute myeloid leukemia [14], [15]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Missense mutation; p.F691L
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Subsequent bidirectional sequencing assay
• Experiment for Drug Resistance: Vi-cell XR automated cell viability analysis
• Mechanism Description: Overall, these data support a primarily structural mechanism for AC220 resistance mediated by mutations at F691, D835 and Y842, although further studies are necessary for definitive confirmation. We speculate that the ability to retain inhibitory activity against activation loop substitutions at D835 and Y842 will require a type I FLT3 kinase inhibitor capable of effectively binding to the active, DFG-in conformation of the kinase.

Disease Class: Acute myeloid leukemia [14]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Missense mutation; p.D835V
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Subsequent bidirectional sequencing assay
• Experiment for Drug Resistance: Vi-cell XR automated cell viability analysis
• Mechanism Description: Overall, these data support a primarily structural mechanism for AC220 resistance mediated by mutations at F691, D835 and Y842, although further studies are necessary for definitive confirmation. We speculate that the ability to retain inhibitory activity against activation loop substitutions at D835 and Y842 will require a type I FLT3 kinase inhibitor capable of effectively binding to the active, DFG-in conformation of the kinase.

Disease Class: Acute myeloid leukemia [14]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Missense mutation; p.D835F
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Subsequent bidirectional sequencing assay
• Experiment for Drug Resistance: Vi-cell XR automated cell viability analysis
• Mechanism Description: Overall, these data support a primarily structural mechanism for AC220 resistance mediated by mutations at F691, D835 and Y842, although further studies are necessary for definitive confirmation. We speculate that the ability to retain inhibitory activity against activation loop substitutions at D835 and Y842 will require a type I FLT3 kinase inhibitor capable of effectively binding to the active, DFG-in conformation of the kinase.

Disease Class: Acute myeloid leukemia [14], [16]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Missense mutation; p.D835Y
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Subsequent bidirectional sequencing assay
• Experiment for Drug Resistance: Vi-cell XR automated cell viability analysis
• Mechanism Description: Overall, these data support a primarily structural mechanism for AC220 resistance mediated by mutations at F691, D835 and Y842, although further studies are necessary for definitive confirmation. We speculate that the ability to retain inhibitory activity against activation loop substitutions at D835 and Y842 will require a type I FLT3 kinase inhibitor capable of effectively binding to the active, DFG-in conformation of the kinase.

Disease Class: Acute myeloid leukemia [9]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Missense mutation; p.F691
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Southern blot analysis; Spectral karyotyping assay
• Mechanism Description: FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.

Disease Class: Acute myeloid leukemia [9]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Missense mutation; p.D835
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Southern blot analysis; Spectral karyotyping assay
• Mechanism Description: FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Mutation; p.Y842C
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The quizartinib IC50 values of cells with Y842C mutation was 106, the quizartinib IC50 value of cells without mutation was 1.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Missense mutation; p.D835Y
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The quizartinib IC50 values of cells with D835Y mutation was 183, the quizartinib IC50 value of cells without mutation was 1.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Missense mutation; p.D835V
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The quizartinib IC50 values of cells with D835V mutation was 563, the quizartinib IC50 value of cells without mutation was 1.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Missense mutation; p.D835I
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The quizartinib IC50 values of cells with D835I mutation was 718, the quizartinib IC50 value of cells without mutation was 1.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Missense mutation; p.D835F
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The quizartinib IC50 values of cells with D835F mutation was 1474, the quizartinib IC50 value of cells without mutation was 1.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Frameshift mutation; p.D835Del
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The quizartinib IC50 values of cells with D835Del mutation was 320, the quizartinib IC50 value of cells without mutation was 1.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Mutation; p.F691L
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The gatekeeper mutation F691L confers resistance to specific FLT3 inhibitors such as quizartinib.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Missense mutation; p.F691L
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The multiple mutations that can confer resistance to quizartinib and pexidartinib. The gatekeeper mutation F691L was the most common mutation in all protocols involving quizartinib; it was rather frequent even with pexidartinib alone.

Disease Class: Acute myeloid leukemia [7]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Missense mutation; p.F691L
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The multiple mutations that can confer resistance to quizartinib and pexidartinib. The gatekeeper mutation F691L was the most common mutation in all protocols involving quizartinib; it was rather frequent even with pexidartinib alone.

Selumetinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [17]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Selumetinib
• Molecule Alteration: IF-deletion; p.Q569_G613 (c.1705_1837)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Blood; .
• Experiment for Molecule Alteration: Gentra puregene assay
• Experiment for Drug Resistance: p-ERK1/2 and p-mTOR analysis

E6201

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute lymphocytic leukemia [18]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Sensitive Drug: E6201
• Molecule Alteration: Missense mutation; p.D835G (c.2504A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: NOG mouse; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion method assay; FACS assay
• Mechanism Description: E6201 exerts marked anti-leukemia effects in AML cells and activation of MEK/ERK signaling pathway by NRAS mutation sensitizes E6201-induced pro-apoptotic effects in AML cells.

Disease Class: Acute myeloid leukemia [18]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: E6201
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: NOG mouse; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion method assay; FACS assay
• Mechanism Description: E6201 exerts marked anti-leukemia effects in AML cells and activation of MEK/ERK signaling pathway by NRAS mutation sensitizes E6201-induced pro-apoptotic effects in AML cells.

Disease Class: Acute myeloid leukemia [18]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: E6201
• Molecule Alteration: Missense mutation; p.D835G (c.2504A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: NOG mouse; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion method assay; FACS assay
• Mechanism Description: E6201 exerts marked anti-leukemia effects in AML cells and activation of MEK/ERK signaling pathway by NRAS mutation sensitizes E6201-induced pro-apoptotic effects in AML cells.

Disease Class: Acute lymphocytic leukemia [18]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Sensitive Drug: E6201
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: NOG mouse; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion method assay; FACS assay
• Mechanism Description: E6201 exerts marked anti-leukemia effects in AML cells and activation of MEK/ERK signaling pathway by NRAS mutation sensitizes E6201-induced pro-apoptotic effects in AML cells.

MRX-2843

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [19]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: MRX-2843
• Molecule Alteration: Missense mutation; p.D835V (c.2504A>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: NOMO-1 cells; Bone marrow; Homo sapiens (Human); CVCL_1609
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: MRX-2843, a type 1 small-molecule tyrosine kinase inhibitor that abrogates activation of both MERTK and FLT3 and their downstream effectors. MRX-2843 treatment induces apoptosis and inhibits colony formation in AML cell lines and primary patient samples expressing MERTK and/or FLT3-ITD, with a wide therapeutic window compared with that of normal human cord blood cells.

Disease Class: Solid tumour/cancer [19]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: MRX-2843
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: NOMO-1 cells; Bone marrow; Homo sapiens (Human); CVCL_1609
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: MRX-2843, a type 1 small-molecule tyrosine kinase inhibitor that abrogates activation of both MERTK and FLT3 and their downstream effectors. MRX-2843 treatment induces apoptosis and inhibits colony formation in AML cell lines and primary patient samples expressing MERTK and/or FLT3-ITD, with a wide therapeutic window compared with that of normal human cord blood cells.

Discontinued Drug(s) 2 drug(s) in total

SU5614

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [20]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: SU5614
• Molecule Alteration: IF-deletion; p.Q569_G613 (c.1705_1837)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The if-deletion p.Q569_G613 (c.1705_1837) in gene FLT3 cause the resistance of SU5614 by unusual activation of pro-survival pathway.

Disease Class: Acute myeloid leukemia [21]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: SU5614
• 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
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.D835Y (c.2503G>T) in gene FLT3 cause the resistance of SU5614 by unusual activation of pro-survival pathway

Tandutinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Acute myeloid leukemia [22]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Tandutinib
• Molecule Alteration: Missense mutation; p.D835V (c.2504A>T)
• 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: Immunoblotting assay
• Experiment for Drug Resistance: Celltiter96AQueousOne solution proliferation assay
• Mechanism Description: The missense mutation p.D835V (c.2504A>T) in gene FLT3 cause the resistance of Tandutinib by aberration of the drug's therapeutic target

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [22]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Tandutinib
• Molecule Alteration: IF-deletion; p.I836delI (c.2508_2510delCAT)
• 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: Immunoblotting assay
• Experiment for Drug Resistance: Celltiter96AQueousOne solution proliferation assay
• Mechanism Description: The if-deletion p.I836delI (c.2508_2510delCAT) in gene FLT3 cause the sensitivity of Tandutinib by aberration of the drug's therapeutic target.

Disease Class: Acute myeloid leukemia [23]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Tandutinib
• Molecule Alteration: Duplication; p.R595_L601 (c.1783_1803)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: KG1a cells; Pleural effusion; Homo sapiens (Human); CVCL_1824
• In Vitro Model: RS4 cells; Bone marrow; Homo sapiens (Human); CVCL_0093
• In Vitro Model: AML193 cells; Peripheral blood; Homo sapiens (Human); CVCL_1071
• In Vivo Model: Athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Kinase assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The duplication p.R595_L601 (c.1783_1803) in gene FLT3 cause the sensitivity of Tandutinib by aberration of the drug's therapeutic target.

Disease Class: Acute myeloid leukemia [23]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Tandutinib
• Molecule Alteration: IF-insertion; p.E598_Y599insGLVQVTGSSDNEYFYVDFREYE (c.1794_1795insGGTCTTGTACAAGTAACAGGTAGCAGCGACAACGAGTATTTTTATGTAGACTTTAGGGAGTATGAG)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: KG1a cells; Pleural effusion; Homo sapiens (Human); CVCL_1824
• In Vitro Model: RS4 cells; Bone marrow; Homo sapiens (Human); CVCL_0093
• In Vitro Model: AML193 cells; Peripheral blood; Homo sapiens (Human); CVCL_1071
• In Vivo Model: Athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Kinase assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The if-insertion p.E598_Y599insGLVQVTGSSDNEYFYVDFREYE (c.1794_1795insGGTCTTGTACAAGTAACAGGTAGCAGCGACAACGAGTATTTTTATGTAGACTTTAGGGAGTATGAG) in gene FLT3 cause the sensitivity of Tandutinib by aberration of the drug's therapeutic target.

Disease Class: Acute myeloid leukemia [23]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Tandutinib
• Molecule Alteration: IF-insertion; p.Y599_D600insGLYVDFREYEY (c.1798_1799insGTCTTTATGTAGACTTTAGGGAGTATGAGTATG)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: KG1a cells; Pleural effusion; Homo sapiens (Human); CVCL_1824
• In Vitro Model: RS4 cells; Bone marrow; Homo sapiens (Human); CVCL_0093
• In Vitro Model: AML193 cells; Peripheral blood; Homo sapiens (Human); CVCL_1071
• In Vivo Model: Athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Kinase assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The if-insertion p.Y599_D600insGLYVDFREYEY (c.1798_1799insGTCTTTATGTAGACTTTAGGGAGTATGAGTATG) in gene FLT3 cause the sensitivity of Tandutinib by aberration of the drug's therapeutic target.

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

Crenolanib/Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Hematologic Cancer [12]

• 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

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

AG1296

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [24]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: AG1296
• Molecule Alteration: IF-deletion; p.Q569_G613 (c.1705_1837)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Experiment for Molecule Alteration: Immunoprecipitation and immunoblot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The if-deletion p.Q569_G613 (c.1705_1837) in gene FLT3 cause the sensitivity of AG1296 by unusual activation of pro-survival pathway.

Disease Class: Acute myeloid leukemia [25]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: AG1296
• Molecule Alteration: Missense mutation; p.D835V (c.2504A>T)
• 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: Cell proliferation Kit II XTT assay
• Mechanism Description: The missense mutation p.D835V (c.2504A>T) in gene FLT3 cause the sensitivity of AG1296 by unusual activation of pro-survival pathway

Azacitidine/Sorafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [26]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Azacitidine/Sorafenib
• Molecule Alteration: IF-insertion; p.Y599_D600insSTDNEYFYVDFREYEY (c.1797_1798insAGCACAGACAACGAGTATTTTTATGTAGACTTTAGGGAGTATGAGTAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Mechanism Description: The if-insertion p.Y599_D600insSTDNEYFYVDFREYEY (c.1797_1798insAGCACAGACAACGAGTATTTTTATGTAGACTTTAGGGAGTATGAGTAT) in gene FLT3 cause the sensitivity of Azacitidine + Sorafenib by unusual activation of pro-survival pathway.

Cytarabine/Daunorubicin/Midostaurin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [27]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Cytarabine/Daunorubicin/Midostaurin
• Molecule Alteration: Missense mutation; p.I836 (c.2506_2508)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Acute myeloid leukemia [27]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Cytarabine/Daunorubicin/Midostaurin
• Molecule Alteration: Missense mutation; p.D835 (c.2503_2505)
• Experimental Note: Identified from the Human Clinical Data

G-749

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Hematologic Cancer [28]

• 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

PD98059

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PD98059
• Molecule Alteration: Missense mutation; p.R834Q (c.2501G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.R834Q (c.2501G>A) in gene FLT3 cause the sensitivity of PD98059 by aberration of the drug's therapeutic target

Tyrosine kinase inhibitor

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Acute myeloid leukemia [29]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Tyrosine kinase inhibitor
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole exome capture sequencing assay
• Experiment for Drug Resistance: karyotyping assay
• Mechanism Description: Treatment with TkIs selectively leads to secondary mutations in the activation loop domain of the gene, where those who relapse after exposure to TkI show evolution of secondary FLT3 mutations that are associated with TkI resistance.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

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: 2.64E-120; Fold-change: 3.41E+00; Z-score: 4.96E+00

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