Disease Information

General Information of the Disease (ID: DIS00199)
Name
Rhabdomyosarcoma
ICD
ICD-11: 2B55
Resistance Map
Type(s) of Resistant Mechanism of This Disease with Structure Alteration
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
Larotrectinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Tropomyosin-related kinase A (TrkA) [1]
Resistant Disease Metastatic undifferentiated sarcoma [ICD-11: 2B55.Y]
Resistant Drug Larotrectinib
 Drug Info 
Molecule Alteration Missense mutation
p.G595R
 Molecule Info 
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
Alpelisib/Binimetinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [2]
Sensitive Disease Alveolar rhabdomyosarcoma [ICD-11: 2B55.0]
Sensitive Drug Alpelisib/Binimetinib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61H (c.183A>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.31  Å
PDB: 6T5V
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6MNX
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.14
TM score: 0.96411
Amino acid change:
Q61H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
C
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
S
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
H
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
L
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
S
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation RAF/MEK/ERK signaling pathway Inhibition hsa04010
PI3K/AKT/mTOR signaling pathway Inhibition hsa04151
In Vitro Model RMS cells Soft tissue Homo sapiens (Human) CVCL_W527
In Vivo Model Chorioallantoic membrane Gallus gallus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; FACS; crystal violet staining
Mechanism Description Coinhibition of NRAS or MEK plus PI3Kalpha triggers widespread apoptosis in NRAS-mutated RMS cells. Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kalpha-specific inhibitor BYL719 synergized to trigger apoptosis in NRAS-mutated RMS cells in vitro and in vivo. NRAS- or HRAS-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than RAS wild-type cell lines, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in NRAS-mutated than RAS wild-type RMS tumors in vivo.
References
Ref 1 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
Ref 2 NRAS-Mutated Rhabdomyosarcoma Cells Are Vulnerable to Mitochondrial Apoptosis Induced by Coinhibition of MEK and PI3KAlphaCancer Res. 2018 Apr 15;78(8):2000-2013. doi: 10.1158/0008-5472.CAN-17-1737. Epub 2018 Feb 6.

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