Drug Information

Drug (ID: DG01683) and It's Reported Resistant Information
Name
Alpelisib/Binimetinib
Synonyms
Alpelisib/Binimetinib
    Click to Show/Hide
Type(s) of Resistant Mechanism of This Drug
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Acute myeloid leukemia [ICD-11: 2A60]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [1]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Molecule Alteration Missense mutation
p.G12D (c.35G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 8JHL
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.9318
Amino acid change:
G12D
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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0
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G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
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G
G
A
A
G
D
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
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T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
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D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
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Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
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T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
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G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
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Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
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C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
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F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
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I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
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P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
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L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
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A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
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P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
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Q
Q
G
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
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V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
K
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NOMO1 cells Bone marrow Homo sapiens (Human) CVCL_1609
BaF3 cells Bone Mus musculus (Mouse) CVCL_0161
THP1 cell Peripheral blood Homo sapiens (Human) CVCL_0006
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay
Rhabdomyosarcoma [ICD-11: 2B55]
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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]
 Disease 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
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M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
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G
G
A
A
C
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
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T
T
I
I
Q
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L
L
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I
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N
N
H
H
F
F
V
V
30
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D
D
E
E
Y
Y
D
D
P
P
T
T
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I
E
E
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D
S
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40
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Y
Y
R
R
K
K
Q
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V
V
V
V
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I
D
D
G
G
E
E
50
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T
T
S
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
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G
G
Q
H
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
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Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
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L
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
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F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
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Q
100
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I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
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P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
S
C
D
D
120
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L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
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A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
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P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
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Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
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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 Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110AlphaJ Clin Invest. 2014 Apr;124(4):1794-809. doi: 10.1172/JCI69927. Epub 2014 Feb 24.
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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