Molecule Information

General Information of the Molecule (ID: Mol01831)
Name
Tropomyosin-related kinase A (TrkA) ,Homo sapiens
Synonyms
Neurotrophic tyrosine kinase receptor type 1; TRK1-transforming tyrosine kinase protein; Tropomyosin-related kinase A; Tyrosine kinase receptor; Tyrosine kinase receptor A; Trk-A; gp140trk; p140-TrkA; NTRK1; MTC; TRK; TRKA
    Click to Show/Hide
Molecule Type
Protein
Gene Name
NTRK1
Gene ID
4914
Location
chr1:156,815,640156,881,850[+]
Sequence
MLRGGRRGQLGWHSWAAGPGSLLAWLILASAGAAPCPDACCPHGSSGLRCTRDGALDSLH
HLPGAENLTELYIENQQHLQHLELRDLRGLGELRNLTIVKSGLRFVAPDAFHFTPRLSRL
NLSFNALESLSWKTVQGLSLQELVLSGNPLHCSCALRWLQRWEEEGLGGVPEQKLQCHGQ
GPLAHMPNASCGVPTLKVQVPNASVDVGDDVLLRCQVEGRGLEQAGWILTELEQSATVMK
SGGLPSLGLTLANVTSDLNRKNVTCWAENDVGRAEVSVQVNVSFPASVQLHTAVEMHHWC
IPFSVDGQPAPSLRWLFNGSVLNETSFIFTEFLEPAANETVRHGCLRLNQPTHVNNGNYT
LLAANPFGQASASIMAAFMDNPFEFNPEDPIPVSFSPVDTNSTSGDPVEKKDETPFGVSV
AVGLAVFACLFLSTLLLVLNKCGRRNKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTE
GKGSGLQGHIIENPQYFSDACVHHIKRRDIVLKWELGEGAFGKVFLAECHNLLPEQDKML
VAVKALKEASESARQDFQREAELLTMLQHQHIVRFFGVCTEGRPLLMVFEYMRHGDLNRF
LRSHGPDAKLLAGGEDVAPGPLGLGQLLAVASQVAAGMVYLAGLHFVHRDLATRNCLVGQ
GLVVKIGDFGMSRDIYSTDYYRVGGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEI
FTYGKQPWYQLSNTEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHAR
LQALAQAPPVYLDVLG
    Click to Show/Hide
3D-structure
PDB ID
7N3T
Classification
De novo protein
Method
X-ray diffraction
Resolution
1.84  Å
Function
Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand. Can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors.; [Isoform TrkA-III]: Resistant to NGF, it constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras-MAPK signaling cascade. Antagonizes the anti-proliferative NGF-NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed.
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Uniprot ID
NTRK1_HUMAN
Ensembl ID
ENSG00000198400
HGNC ID
HGNC:8031
        Click to Show/Hide the Complete Species Lineage
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)
2 drug(s) in total
Click to Show/Hide the Full List of Drugs
Entrectinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Colorectal cancer [ICD-11: 2B91.1] [2]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Resistant Drug Entrectinib
 Drug Info 
Molecule Alteration Missense mutation
p.G595R (c.1783G>A)
Wild Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 5H3Q
Mutant Type Structure Method: X-ray diffraction Resolution: 2.09  Å
PDB: 8J5X
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.93325
Amino acid change:
G595R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model KM-12 cells Colon Homo sapiens (Human) CVCL_1331
In Vivo Model NOD-SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 ddPCR; Kinase domain alignment assay
Disease Class: Colorectal cancer [ICD-11: 2B91.1] [2]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Resistant Drug Entrectinib
 Drug Info 
Molecule Alteration Missense mutation
p.G667C (c.1999G>T)
Experimental Note Identified from the Human Clinical Data
In Vitro Model KM-12 cells Colon Homo sapiens (Human) CVCL_1331
In Vivo Model NOD-SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 ddPCR; Kinase domain alignment assay
Disease Class: Glioma [ICD-11: 2A00.1] [1]
Resistant Disease Glioma [ICD-11: 2A00.1]
 Disease Info 
Resistant Drug Entrectinib
 Drug Info 
Molecule Alteration Missense mutation
F589L; G595R; G667C; F589L-G595R
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NIH-3T3-tv-a cells Embryo Homo sapiens (Human) N.A.
In Vivo Model RCAS/tv-a system 19. Nestin (N)/tv-a mouse model; Cdkn2a-wild type mouse model; Null mice model Mus musculus
Experiment for
Molecule Alteration		 Western blot assay; RT-PCR
Experiment for
Drug Resistance		 Quantification of Larotrectinib tissue levels assay; Spheroid assay; Magnetic resonance imaging assay; H&E staining assay; Immunohistochemistry staining assay
Mechanism Description Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors.
Larotrectinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Colorectal cancer [ICD-11: 2B91.1] [3]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Resistant Drug Larotrectinib
 Drug Info 
Molecule Alteration Missense mutation
p.G595R (c.1783G>A)
Wild Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 5H3Q
Mutant Type Structure Method: X-ray diffraction Resolution: 2.09  Å
PDB: 8J5X
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.93325
Amino acid change:
G595R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
KM-12 cells Colon Homo sapiens (Human) CVCL_1331
In Vivo Model Balb-c nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Sanger sequencing assay; Western blot analysis
Experiment for
Drug Resistance		 CellTiter Glo assay; IC50 assay
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [4]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug Larotrectinib
 Drug Info 
Molecule Alteration Missense mutation
p.G595R (c.1783G>A)
Wild Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 5H3Q
Mutant Type Structure Method: X-ray diffraction Resolution: 2.09  Å
PDB: 8J5X
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.93325
Amino acid change:
G595R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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570
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Q
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600
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F
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610
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Q
Q
L
L
L
L
A
A
630
|
V
V
A
A
S
S
Q
Q
V
V
A
A
A
A
G
G
M
M
V
V
640
|
Y
Y
L
L
A
A
G
G
L
L
H
H
F
F
V
V
H
H
R
R
650
|
D
D
L
L
A
A
T
T
R
R
N
N
C
C
L
L
V
V
G
G
660
|
Q
Q
G
G
L
L
V
V
V
V
K
K
I
I
G
G
D
D
F
F
670
|
G
G
M
M
S
S
R
R
D
D
I
I
Y
Y
S
S
T
T
D
D
680
|
Y
Y
Y
Y
R
R
V
V
G
G
G
G
R
R
T
T
M
M
L
L
690
|
P
P
I
I
R
R
W
W
M
M
P
P
P
P
E
E
S
S
I
I
700
|
L
L
Y
Y
R
R
K
K
F
F
T
T
T
T
E
E
S
S
D
D
710
|
V
V
W
W
S
S
F
F
G
G
V
V
V
V
L
L
W
W
E
E
720
|
I
I
F
F
T
T
Y
Y
G
G
K
K
Q
Q
P
P
W
W
Y
Y
730
|
Q
Q
L
L
S
S
N
N
T
T
E
E
A
A
I
I
D
D
C
C
740
|
I
I
T
T
Q
Q
G
G
R
R
E
E
L
L
E
E
R
R
P
P
750
|
R
R
A
A
C
C
P
P
P
P
E
E
V
V
Y
Y
A
A
I
I
760
|
M
M
R
R
G
G
C
C
W
W
Q
Q
R
R
E
E
P
P
Q
Q
770
|
Q
Q
R
R
H
H
S
S
I
I
K
K
D
D
V
V
H
H
A
A
780
|
R
R
L
L
Q
Q
A
A
L
L
A
A
Q
Q
A
A
P
P
P
P
790
|
V
V
Y
Y
L
L
D
D
V
V
L
L
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Disease Class: Colorectal cancer [ICD-11: 2B91.1] [3]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Resistant Drug Larotrectinib
 Drug Info 
Molecule Alteration Missense mutation
p.G667C (c.1999G>T)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
KM-12 cells Colon Homo sapiens (Human) CVCL_1331
In Vivo Model Balb-c nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Sanger sequencing assay; Western blot analysis
Experiment for
Drug Resistance		 CellTiter Glo assay; IC50 assay
Disease Class: Glioma [ICD-11: 2A00.1] [1]
Resistant Disease Glioma [ICD-11: 2A00.1]
 Disease Info 
Resistant Drug Larotrectinib
 Drug Info 
Molecule Alteration Missense mutation
F589L; G595R; F589L-G595R
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NIH-3T3-tv-a cells Embryo Homo sapiens (Human) N.A.
In Vivo Model RCAS/tv-a system 19. Nestin (N)/tv-a mouse model; Cdkn2a-wild type mouse model; Null mice model Mus musculus
Experiment for
Molecule Alteration		 Western blot assay; RT-PCR
Experiment for
Drug Resistance		 Quantification of Larotrectinib tissue levels assay; Spheroid assay; Magnetic resonance imaging assay; H&E staining assay; Immunohistochemistry staining assay
Mechanism Description Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Metastatic undifferentiated sarcoma [ICD-11: 2B55.Y] [5]
Resistant Disease Metastatic undifferentiated sarcoma [ICD-11: 2B55.Y]
 Disease Info 
Resistant Drug Larotrectinib
 Drug Info 
Molecule Alteration Missense mutation
p.G595R
Wild Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 5H3Q
Mutant Type Structure Method: X-ray diffraction Resolution: 2.09  Å
PDB: 8J5X
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.93325
Amino acid change:
G595R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
S
-
L
-
S
-
P
-
T
-
480
|
E
-
G
-
K
-
G
-
S
-
G
-
L
-
Q
-
G
-
H
-
490
|
I
-
I
-
E
-
N
-
P
-
Q
-
Y
-
F
-
S
S
D
D
500
|
A
A
C
C
V
V
H
H
H
H
I
I
K
K
R
R
R
R
D
D
510
|
I
I
V
V
L
L
K
K
W
W
E
E
L
L
G
G
E
E
G
G
520
|
A
A
F
F
G
G
K
K
V
V
F
F
L
L
A
A
E
E
C
C
530
|
H
H
N
N
L
L
L
L
P
P
E
E
Q
Q
D
D
K
K
M
M
540
|
L
L
V
V
A
A
V
V
K
K
A
A
L
L
K
K
E
E
A
A
550
|
S
S
E
E
S
S
A
A
R
R
Q
Q
D
D
F
F
Q
Q
R
R
560
|
E
E
A
A
E
E
L
L
L
L
T
T
M
M
L
L
Q
Q
H
H
570
|
Q
Q
H
H
I
I
V
V
R
R
F
F
F
F
G
G
V
V
C
C
580
|
T
T
E
E
G
G
R
R
P
P
L
L
L
L
M
M
V
V
F
F
590
|
E
E
Y
Y
M
M
R
R
H
H
G
R
D
D
L
L
N
N
R
R
600
|
F
F
L
L
R
R
S
S
H
H
G
G
P
P
D
D
A
A
K
K
610
|
L
L
L
L
A
A
G
G
G
G
E
E
D
D
V
V
A
A
P
P
620
|
G
G
P
P
L
L
G
G
L
L
G
G
Q
Q
L
L
L
L
A
A
630
|
V
V
A
A
S
S
Q
Q
V
V
A
A
A
A
G
G
M
M
V
V
640
|
Y
Y
L
L
A
A
G
G
L
L
H
H
F
F
V
V
H
H
R
R
650
|
D
D
L
L
A
A
T
T
R
R
N
N
C
C
L
L
V
V
G
G
660
|
Q
Q
G
G
L
L
V
V
V
V
K
K
I
I
G
G
D
D
F
F
670
|
G
G
M
M
S
S
R
R
D
D
I
I
Y
Y
S
S
T
T
D
D
680
|
Y
Y
Y
Y
R
R
V
V
G
G
G
G
R
R
T
T
M
M
L
L
690
|
P
P
I
I
R
R
W
W
M
M
P
P
P
P
E
E
S
S
I
I
700
|
L
L
Y
Y
R
R
K
K
F
F
T
T
T
T
E
E
S
S
D
D
710
|
V
V
W
W
S
S
F
F
G
G
V
V
V
V
L
L
W
W
E
E
720
|
I
I
F
F
T
T
Y
Y
G
G
K
K
Q
Q
P
P
W
W
Y
Y
730
|
Q
Q
L
L
S
S
N
N
T
T
E
E
A
A
I
I
D
D
C
C
740
|
I
I
T
T
Q
Q
G
G
R
R
E
E
L
L
E
E
R
R
P
P
750
|
R
R
A
A
C
C
P
P
P
P
E
E
V
V
Y
Y
A
A
I
I
760
|
M
M
R
R
G
G
C
C
W
W
Q
Q
R
R
E
E
P
P
Q
Q
770
|
Q
Q
R
R
H
H
S
S
I
I
K
K
D
D
V
V
H
H
A
A
780
|
R
R
L
L
Q
Q
A
A
L
L
A
A
Q
Q
A
A
P
P
P
P
790
|
V
V
Y
Y
L
L
D
D
V
V
L
L
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model NTHY-ORI-3-1 cells Thyroid gland Homo sapiens (Human) CVCL_2659
Mechanism Description After 6 months on study, restaging scans identified an isolated area of progression in the right hepatic lobe, which was resected (S3), followed by resumption of larotrectinib. NGS from S3 identified an NTRK1 G595R solvent-front mutation. Three months later, diffuse disease was noted on restaging scans.
Preclinical Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
Pan-TRK inhibitors
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Colorectal cancer [ICD-11: 2B91.1] [2]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Resistant Drug Pan-TRK inhibitors
 Drug Info 
Molecule Alteration Missense mutation
p.G595R (c.1783G>A)
Wild Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 5H3Q
Mutant Type Structure Method: X-ray diffraction Resolution: 2.09  Å
PDB: 8J5X
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.93325
Amino acid change:
G595R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
S
-
L
-
S
-
P
-
T
-
480
|
E
-
G
-
K
-
G
-
S
-
G
-
L
-
Q
-
G
-
H
-
490
|
I
-
I
-
E
-
N
-
P
-
Q
-
Y
-
F
-
S
S
D
D
500
|
A
A
C
C
V
V
H
H
H
H
I
I
K
K
R
R
R
R
D
D
510
|
I
I
V
V
L
L
K
K
W
W
E
E
L
L
G
G
E
E
G
G
520
|
A
A
F
F
G
G
K
K
V
V
F
F
L
L
A
A
E
E
C
C
530
|
H
H
N
N
L
L
L
L
P
P
E
E
Q
Q
D
D
K
K
M
M
540
|
L
L
V
V
A
A
V
V
K
K
A
A
L
L
K
K
E
E
A
A
550
|
S
S
E
E
S
S
A
A
R
R
Q
Q
D
D
F
F
Q
Q
R
R
560
|
E
E
A
A
E
E
L
L
L
L
T
T
M
M
L
L
Q
Q
H
H
570
|
Q
Q
H
H
I
I
V
V
R
R
F
F
F
F
G
G
V
V
C
C
580
|
T
T
E
E
G
G
R
R
P
P
L
L
L
L
M
M
V
V
F
F
590
|
E
E
Y
Y
M
M
R
R
H
H
G
R
D
D
L
L
N
N
R
R
600
|
F
F
L
L
R
R
S
S
H
H
G
G
P
P
D
D
A
A
K
K
610
|
L
L
L
L
A
A
G
G
G
G
E
E
D
D
V
V
A
A
P
P
620
|
G
G
P
P
L
L
G
G
L
L
G
G
Q
Q
L
L
L
L
A
A
630
|
V
V
A
A
S
S
Q
Q
V
V
A
A
A
A
G
G
M
M
V
V
640
|
Y
Y
L
L
A
A
G
G
L
L
H
H
F
F
V
V
H
H
R
R
650
|
D
D
L
L
A
A
T
T
R
R
N
N
C
C
L
L
V
V
G
G
660
|
Q
Q
G
G
L
L
V
V
V
V
K
K
I
I
G
G
D
D
F
F
670
|
G
G
M
M
S
S
R
R
D
D
I
I
Y
Y
S
S
T
T
D
D
680
|
Y
Y
Y
Y
R
R
V
V
G
G
G
G
R
R
T
T
M
M
L
L
690
|
P
P
I
I
R
R
W
W
M
M
P
P
P
P
E
E
S
S
I
I
700
|
L
L
Y
Y
R
R
K
K
F
F
T
T
T
T
E
E
S
S
D
D
710
|
V
V
W
W
S
S
F
F
G
G
V
V
V
V
L
L
W
W
E
E
720
|
I
I
F
F
T
T
Y
Y
G
G
K
K
Q
Q
P
P
W
W
Y
Y
730
|
Q
Q
L
L
S
S
N
N
T
T
E
E
A
A
I
I
D
D
C
C
740
|
I
I
T
T
Q
Q
G
G
R
R
E
E
L
L
E
E
R
R
P
P
750
|
R
R
A
A
C
C
P
P
P
P
E
E
V
V
Y
Y
A
A
I
I
760
|
M
M
R
R
G
G
C
C
W
W
Q
Q
R
R
E
E
P
P
Q
Q
770
|
Q
Q
R
R
H
H
S
S
I
I
K
K
D
D
V
V
H
H
A
A
780
|
R
R
L
L
Q
Q
A
A
L
L
A
A
Q
Q
A
A
P
P
P
P
790
|
V
V
Y
Y
L
L
D
D
V
V
L
L
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model KM-12 cells Colon Homo sapiens (Human) CVCL_1331
In Vivo Model NOD-SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 ddPCR; Kinase domain alignment assay
Disease Class: Colorectal cancer [ICD-11: 2B91.1] [2]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Resistant Drug Pan-TRK inhibitors
 Drug Info 
Molecule Alteration Missense mutation
p.G667C (c.1999G>T)
Experimental Note Identified from the Human Clinical Data
In Vitro Model KM-12 cells Colon Homo sapiens (Human) CVCL_1331
In Vivo Model NOD-SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 ddPCR; Kinase domain alignment assay
References
Ref 1 ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models. Cell Rep. 2024 Oct 22;43(10):114829.
Ref 2 Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal CancerCancer Discov. 2016 Jan;6(1):36-44. doi: 10.1158/2159-8290.CD-15-0940. Epub 2015 Nov 6.
Ref 3 Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged CancersMol Cancer Ther. 2017 Oct;16(10):2130-2143. doi: 10.1158/1535-7163.MCT-16-0909. Epub 2017 Jul 27.
Ref 4 A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid TumorsCancer Discov. 2017 Sep;7(9):963-972. doi: 10.1158/2159-8290.CD-17-0507. Epub 2017 Jun 3.
Ref 5 Response and mechanisms of resistance to larotrectinib and selitrectinib in metastatic undifferentiated sarcoma harboring oncogenic fusion of NTRK1 .JCO Precis Oncol. 2020;4:79-90. doi: 10.1200/po.19.00287. Epub 2020 Feb 14. 10.1200/po.19.00287

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