Drug Information

Drug (ID: DG01733) and It's Reported Resistant Information
Name
Buparlisib/Osimertinib
Synonyms
Buparlisib/Osimertinib
    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
Lung cancer [ICD-11: 2C25]
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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: Epidermal growth factor receptor (EGFR) [1]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Missense mutation
p.L858R (c.2573T>G)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.64  Å
PDB: 4LI5
Mutant Type Structure Method: X-ray diffraction Resolution: 2.47  Å
PDB: 2ITV
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.90001
Amino acid change:
L858R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
M
-
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
T
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
R
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
-
Q
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Axon guidance signaling pathway Inhibition hsa04360
MAPK signaling pathway Inhibition hsa04010
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
NCI-H1975 cells Lung Homo sapiens (Human) CVCL_1511
HCC4006 cells Lung Homo sapiens (Human) CVCL_1269
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NCI-H3255 cells Lung Homo sapiens (Human) CVCL_6831
11-18 cells Lung Homo sapiens (Human) CVCL_6659
In Vivo Model Athymic female mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Src family kinases (SFK) and focal adhesion kinase (FAK) sustain AKT and mitogen-activated protein kinase (MAPK) pathway signaling under continuous EGFR inhibition in osimertinib sensitive cells. Inhibiting either the MAPK pathway or the AKT pathway enhanced the effects of osimertinib. Combined SFK/FAK inhibition exhibited the most potent effects on growth inhibition, induction of apoptosis, and delay of acquired resistance. SFK family member YES1 was amplified in osimertinib- resistant EGFR-mutant tumor cells, the effects of which were overcome by combined treatment with osimertinib and SFK inhibitors.
References
Ref 1 SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung CancerCancer Res. 2017 Jun 1;77(11):2990-3000. doi: 10.1158/0008-5472.CAN-16-2300. Epub 2017 Apr 17.

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