Drug Information

Drug (ID: DG00677) and It's Reported Resistant Information
Name
Trametinib
Synonyms
Trametinib; 871700-17-3; GSK1120212; Mekinist; GSK-1120212; JTP 74057; JTP-74057; GSK 1120212; Trametinib (GSK1120212); N-[3-[3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]acetamide; GSK212; UNII-33E86K87QN; TMT212; CHEBI:75998; TMT-212; 33E86K87QN; N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide; N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide; N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide; Trametinib [USAN:INN]; trametinibum; JTP74057; N-(3-(3-Cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido(4,3-d)pyrimidin-1(2H)-yl)phenyl)acetamide; N-(3-{3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido(4,3-d)pyrimidin-1(2H)-yl}phenyl)acetamide; QOM; Trametinib (USAN); Trametinib (GSK1120212JTP 74057); SCHEMBL170938; C26H23FIN5O4; GTPL6495; QCR-39; GSK1120212 (Trametinib); CHEMBL2103875; EX-A022; BCPP000218; DTXSID901007381; HMS3295I05; HMS3656J11; AOB87707; BCP02307; BDBM50531540; MFCD17215075; NSC758246; NSC800956; s2673; ZINC43100709; AKOS015850628; AM90271; CCG-264976; CS-0060; DB08911; EX-5957; NSC-758246; NSC-800956; SB16553; NCGC00263180-01; NCGC00263180-07; NCGC00263180-14; AC-25891; AS-19382; HY-10999; N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-2,4,7-trioxo-pyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide; FT-0688438; SW218089-2; X7454; A25168; D10175; GSK1120212 - JTP-74057; GSK1120212,JTP-74057, GSK212; SR-01000941589; A1-01871; J-523325; Q7833138; SR-01000941589-1; BRD-K12343256-001-01-4; Acetamide, N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-3,4,6,7-tetrahydro-6,8- dimethyl-2,4,7-trioxopyrido(4,3-d)pyrimidin-1(2H)-yl)phenyl)-; Acetamide, N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]-; N-(3-(3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide; N-[3-[3-Cyclopropyl-5-[(2-Fluoro-4-Iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2h)-yl]phe nyl]acetamide; N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxopyrido[3,4-e]pyrimidin-1-yl]phenyl]acetamide; N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}ethanimidic acid; N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide
    Click to Show/Hide
Indication
In total 1 Indication(s)
Melanoma [ICD-11: 2C30]
Approved
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
Esophageal cancer [ICD-11: 2B70]
[2]
Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
Melanoma [ICD-11: 2C30]
[3]
Neurofibromatoses [ICD-11: LD2D]
[4]
Pancreatic cancer [ICD-11: 2C10]
[5]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Head and neck cancer [ICD-11: 2D42]
[1]
Target MAPK/ERK kinase kinase (MAP3K) NOUNIPROTAC [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C26H23FIN5O4
IsoSMILES
CC1=C2C(=C(N(C1=O)C)NC3=C(C=C(C=C3)I)F)C(=O)N(C(=O)N2C4=CC=CC(=C4)NC(=O)C)C5CC5
InChI
1S/C26H23FIN5O4/c1-13-22-21(23(31(3)24(13)35)30-20-10-7-15(28)11-19(20)27)25(36)33(17-8-9-17)26(37)32(22)18-6-4-5-16(12-18)29-14(2)34/h4-7,10-12,17,30H,8-9H2,1-3H3,(H,29,34)
InChIKey
LIRYPHYGHXZJBZ-UHFFFAOYSA-N
PubChem CID
11707110
ChEBI ID
CHEBI:75998
TTD Drug ID
D04XVN
DrugBank ID
DB08911
Type(s) of Resistant Mechanism of This Drug
  ADTT: Aberration of the Drug's Therapeutic Target
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  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
Head and neck cancer [ICD-11: 2D42]
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: Transcriptional coactivator YAP1 (YAP1) [1]
Resistant Disease Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Head and neck cancer [ICD-11: 2D42]
The Specified Disease Head and neck cancer
The Studied Tissue Head and neck tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 9.28E-01
Fold-change: 1.06E-03
Z-score: 8.99E-02
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
RkO cells Colon Homo sapiens (Human) CVCL_0504
SH-1-V5 cells Esophagus Homo sapiens (Human) N.A.
In Vivo Model Patient-derived xenografts in female NSG mouse model Mus musculus
Mechanism Description Yap1 Mediates Trametinib Resistance in Head and Neck Squamous Cell Carcinomas. This study identify a Yap1-dependent resistance to trametinib therapy in HNSCCs. Combined Yap1 and MEK targeting may represent a strategy to enhance HNSCC response.
Brain cancer [ICD-11: 2A00]
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: CREB-regulated transcription coactivator 1 (CRTC1) [6]
Sensitive Disease Glioblastoma [ICD-11: 2A00.02]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
TORC1 signaling pathway Regulation N.A.
In Vitro Model BT-40 cells Brain Homo sapiens (Human) N.A.
NCH-MN-1 cells Brain Homo sapiens (Human) N.A.
IC-3635 cells Brain Homo sapiens (Human) N.A.
In Vivo Model C.B.17SC scid?/? mice model Mus musculus
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 Clonogenic assay; Cellular viability assay; In vivo tumor growth inhibition assay; Orthotopic xenograft assay
Mechanism Description In pediatric models TORC1 is activated through ERK-mediated inactivation of the tuberous sclerosis complex (TSC): consequently inhibition of MEK also suppressed TORC1 signaling. Trametinib-induced tumor regression correlated with dual inhibition of MAPK/TORC1 signaling, and decoupling TORC1 regulation from BRAF/MAPK control conferred trametinib resistance. TORC1 signaling is controlled by the MAPK cascade. Trametinib suppressed both MAPK/TORC1 pathways leading to tumor regression. While low-dose intermittent rapamycin to enhance inhibition of TORC1 only modestly enhanced the antitumor activity of trametinib, it prevented or retarded development of trametinib resistance.
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: MAPK/ERK kinase 1 (MEK1) [7]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.Q56P (c.167A>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
AGS cells Gastric Homo sapiens (Human) CVCL_0139
NCI-N87 cells Gastric Homo sapiens (Human) CVCL_1603
NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
SW48 cells Colon Homo sapiens (Human) CVCL_1724
A549 cells Lung Homo sapiens (Human) CVCL_0023
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-H1650 cells Lung Homo sapiens (Human) CVCL_1483
SW1573 cells Lung Homo sapiens (Human) CVCL_1720
SNU-C1 cells Peritoneum Homo sapiens (Human) CVCL_1708
OCUM-1 cells Pleural effusion Homo sapiens (Human) CVCL_3084
NCI-H226 cells Pleural effusion Homo sapiens (Human) CVCL_1544
NCI-H196 cells Pleural effusion Homo sapiens (Human) CVCL_1509
NCI-H1437 cells Pleural effusion Homo sapiens (Human) CVCL_1472
NCI-H1355 cells Pleural effusion Homo sapiens (Human) CVCL_1464
MKN7 cells Lymph node Homo sapiens (Human) CVCL_1417
NCI-H1299 cells Lymph node Homo sapiens (Human) CVCL_0060
HCC366 cells Lung Homo sapiens (Human) CVCL_2059
NCI-H2126 cells Pleural effusion Homo sapiens (Human) CVCL_1532
In Vivo Model Female nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: PI3-kinase alpha (PIK3CA) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.H1047R (c.3140A>G)
 Molecule Info 
Wild Type Structure Method: Electron microscopy Resolution: 2.41  Å
PDB: 8DCP
Mutant Type Structure Method: X-ray diffraction Resolution: 2.61  Å
PDB: 8V8V
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.09
TM score: 0.95656
Amino acid change:
H1047R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
-
S
-
Y
-
Y
-
H
-
H
-
H
-
-20
|
H
-
H
-
H
-
D
-
Y
-
D
-
I
-
P
-
T
-
T
-
-10
|
E
-
N
-
L
-
Y
-
F
-
Q
-
G
G
A
A
M
M
G
G
0
|
S
S
M
M
P
P
P
P
R
R
P
P
S
S
S
S
G
G
E
E
10
|
L
L
W
W
G
G
I
I
H
H
L
L
M
M
P
P
P
P
R
R
20
|
I
I
L
L
V
V
E
E
C
C
L
L
L
L
P
P
N
N
G
G
30
|
M
M
I
I
V
V
T
T
L
L
E
E
C
C
L
L
R
R
E
E
40
|
A
A
T
T
L
L
I
I
T
T
I
I
K
K
H
H
E
E
L
L
50
|
F
F
K
K
E
E
A
A
R
R
K
K
Y
Y
P
P
L
L
H
H
60
|
Q
Q
L
L
L
L
Q
Q
D
D
E
E
S
S
S
S
Y
Y
I
I
70
|
F
F
V
V
S
S
V
V
T
T
Q
Q
E
E
A
A
E
E
R
R
80
|
E
E
E
E
F
F
F
F
D
D
E
E
T
T
R
R
R
R
L
L
90
|
C
C
D
D
L
L
R
R
L
L
F
F
Q
Q
P
P
F
F
L
L
100
|
K
K
V
V
I
I
E
E
P
P
V
V
G
G
N
N
R
R
E
E
110
|
E
E
K
K
I
I
L
L
N
N
R
R
E
E
I
I
G
G
F
F
120
|
A
A
I
I
G
G
M
M
P
P
V
V
C
C
E
E
F
F
D
D
130
|
M
M
V
V
K
K
D
D
P
P
E
E
V
V
Q
Q
D
D
F
F
140
|
R
R
R
R
N
N
I
I
L
L
N
N
V
V
C
C
K
K
E
E
150
|
A
A
V
V
D
D
L
L
R
R
D
D
L
L
N
N
S
S
P
P
160
|
H
H
S
S
R
R
A
A
M
M
Y
Y
V
V
Y
Y
P
P
P
P
170
|
N
N
V
V
E
E
S
S
S
S
P
P
E
E
L
L
P
P
K
K
180
|
H
H
I
I
Y
Y
N
N
K
K
L
L
D
D
K
K
G
G
Q
Q
190
|
I
I
I
I
V
V
V
V
I
I
W
W
V
V
I
I
V
V
S
S
200
|
P
P
N
N
N
N
D
D
K
K
Q
Q
K
K
Y
Y
T
T
L
L
210
|
K
K
I
I
N
N
H
H
D
D
C
C
V
V
P
P
E
E
Q
Q
220
|
V
V
I
I
A
A
E
E
A
A
I
I
R
R
K
K
K
K
T
T
230
|
R
R
S
S
M
M
L
L
L
L
S
S
S
S
E
E
Q
Q
L
L
240
|
K
K
L
L
C
C
V
V
L
L
E
E
Y
Y
Q
Q
G
G
K
K
250
|
Y
Y
I
I
L
L
K
K
V
V
C
C
G
G
C
C
D
D
E
E
260
|
Y
Y
F
F
L
L
E
E
K
K
Y
Y
P
P
L
L
S
S
Q
Q
270
|
Y
Y
K
K
Y
Y
I
I
R
R
S
S
C
C
I
I
M
M
L
L
280
|
G
G
R
R
M
M
P
P
N
N
L
L
M
M
L
L
M
M
A
A
290
|
K
K
E
E
S
S
L
L
Y
Y
S
S
Q
Q
L
L
P
P
M
M
300
|
D
D
C
C
F
F
T
T
M
M
P
P
S
S
Y
Y
S
S
R
R
310
|
R
R
I
I
S
S
T
T
A
A
T
T
P
P
Y
Y
M
M
N
N
320
|
G
G
E
E
T
T
S
S
T
T
K
K
S
S
L
L
W
W
V
V
330
|
I
I
N
N
S
S
A
A
L
L
R
R
I
I
K
K
I
I
L
L
340
|
C
C
A
A
T
T
Y
Y
V
V
N
N
V
V
N
N
I
I
R
R
350
|
D
D
I
I
D
D
K
K
I
I
Y
Y
V
V
R
R
T
T
G
G
360
|
I
I
Y
Y
H
H
G
G
G
G
E
E
P
P
L
L
C
C
D
D
370
|
N
N
V
V
N
N
T
T
Q
Q
R
R
V
V
P
P
C
C
S
S
380
|
N
N
P
P
R
R
W
W
N
N
E
E
W
W
L
L
N
N
Y
Y
390
|
D
D
I
I
Y
Y
I
I
P
P
D
D
L
L
P
P
R
R
A
A
400
|
A
A
R
R
L
L
C
C
L
L
S
S
I
I
C
C
S
S
V
V
410
|
K
K
G
G
R
R
K
K
G
G
A
A
K
K
E
E
E
E
H
H
420
|
C
C
P
P
L
L
A
A
W
W
G
G
N
N
I
I
N
N
L
L
430
|
F
F
D
D
Y
Y
T
T
D
D
T
T
L
L
V
V
S
S
G
G
440
|
K
K
M
M
A
A
L
L
N
N
L
L
W
W
P
P
V
V
P
P
450
|
H
H
G
G
L
L
E
E
D
D
L
L
L
L
N
N
P
P
I
I
460
|
G
G
V
V
T
T
G
G
S
S
N
N
P
P
N
N
K
K
E
E
470
|
T
T
P
P
C
C
L
L
E
E
L
L
E
E
F
F
D
D
W
W
480
|
F
F
S
S
S
S
V
V
V
V
K
K
F
F
P
P
D
D
M
M
490
|
S
S
V
V
I
I
E
E
E
E
H
H
A
A
N
N
W
W
S
S
500
|
V
V
S
S
R
R
E
E
A
A
G
G
F
F
S
S
Y
Y
S
S
510
|
H
H
A
A
G
G
L
L
S
S
N
N
R
R
L
L
A
A
R
R
520
|
D
D
N
N
E
E
L
L
R
R
E
E
N
N
D
D
K
K
E
E
530
|
Q
Q
L
L
K
K
A
A
I
I
S
S
T
T
R
R
D
D
P
P
540
|
L
L
S
S
E
E
I
I
T
T
E
E
Q
Q
E
E
K
K
D
D
550
|
F
F
L
L
W
W
S
S
H
H
R
R
H
H
Y
Y
C
C
V
V
560
|
T
T
I
I
P
P
E
E
I
I
L
L
P
P
K
K
L
L
L
L
570
|
L
L
S
S
V
V
K
K
W
W
N
N
S
S
R
R
D
D
E
E
580
|
V
V
A
A
Q
Q
M
M
Y
Y
C
C
L
L
V
V
K
K
D
D
590
|
W
W
P
P
P
P
I
I
K
K
P
P
E
E
Q
Q
A
A
M
M
600
|
E
E
L
L
L
L
D
D
C
C
N
N
Y
Y
P
P
D
D
P
P
610
|
M
M
V
V
R
R
G
G
F
F
A
A
V
V
R
R
C
C
L
L
620
|
E
E
K
K
Y
Y
L
L
T
T
D
D
D
D
K
K
L
L
S
S
630
|
Q
Q
Y
Y
L
L
I
I
Q
Q
L
L
V
V
Q
Q
V
V
L
L
640
|
K
K
Y
Y
E
E
Q
Q
Y
Y
L
L
D
D
N
N
L
L
L
L
650
|
V
V
R
R
F
F
L
L
L
L
K
K
K
K
A
A
L
L
T
T
660
|
N
N
Q
Q
R
R
I
I
G
G
H
H
F
F
F
F
F
F
W
W
670
|
H
H
L
L
K
K
S
S
E
E
M
M
H
H
N
N
K
K
T
T
680
|
V
V
S
S
Q
Q
R
R
F
F
G
G
L
L
L
L
L
L
E
E
690
|
S
S
Y
Y
C
C
R
R
A
A
C
C
G
G
M
M
Y
Y
L
L
700
|
K
K
H
H
L
L
N
N
R
R
Q
Q
V
V
E
E
A
A
M
M
710
|
E
E
K
K
L
L
I
I
N
N
L
L
T
T
D
D
I
I
L
L
720
|
K
K
Q
Q
E
E
K
K
K
K
D
D
E
E
T
T
Q
Q
K
K
730
|
V
V
Q
Q
M
M
K
K
F
F
L
L
V
V
E
E
Q
Q
M
M
740
|
R
R
R
R
P
P
D
D
F
F
M
M
D
D
A
A
L
L
Q
Q
750
|
G
G
F
F
L
L
S
S
P
P
L
L
N
N
P
P
A
A
H
H
760
|
Q
Q
L
L
G
G
N
N
L
L
R
R
L
L
E
E
E
E
C
C
770
|
R
R
I
I
M
M
S
S
S
S
A
A
K
K
R
R
P
P
L
L
780
|
W
W
L
L
N
N
W
W
E
E
N
N
P
P
D
D
I
I
M
M
790
|
S
S
E
E
L
L
L
L
F
F
Q
Q
N
N
N
N
E
E
I
I
800
|
I
I
F
F
K
K
N
N
G
G
D
D
D
D
L
L
R
R
Q
Q
810
|
D
D
M
M
L
L
T
T
L
L
Q
Q
I
I
I
I
R
R
I
I
820
|
M
M
E
E
N
N
I
I
W
W
Q
Q
N
N
Q
Q
G
G
L
L
830
|
D
D
L
L
R
R
M
M
L
L
P
P
Y
Y
G
G
C
C
L
L
840
|
S
S
I
I
G
G
D
D
C
C
V
V
G
G
L
L
I
I
E
E
850
|
V
V
V
V
R
R
N
N
S
S
H
H
T
T
I
I
M
M
Q
Q
860
|
I
I
Q
Q
C
C
K
K
G
G
G
G
L
L
K
K
G
G
A
A
870
|
L
L
Q
Q
F
F
N
N
S
S
H
H
T
T
L
L
H
H
Q
Q
880
|
W
W
L
L
K
K
D
D
K
K
N
N
K
K
G
G
E
E
I
I
890
|
Y
Y
D
D
A
A
A
A
I
I
D
D
L
L
F
F
T
T
R
R
900
|
S
S
C
C
A
A
G
G
Y
Y
C
C
V
V
A
A
T
T
F
F
910
|
I
I
L
L
G
G
I
I
G
G
D
D
R
R
H
H
N
N
S
S
920
|
N
N
I
I
M
M
V
V
K
K
D
D
D
D
G
G
Q
Q
L
L
930
|
F
F
H
H
I
I
D
D
F
F
G
G
H
H
F
F
L
L
D
D
940
|
H
H
K
K
K
K
K
K
K
K
F
F
G
G
Y
Y
K
K
R
R
950
|
E
E
R
R
V
V
P
P
F
F
V
V
L
L
T
T
Q
Q
D
D
960
|
F
F
L
L
I
I
V
V
I
I
S
S
K
K
G
G
A
A
Q
Q
970
|
E
E
C
C
T
T
K
K
T
T
R
R
E
E
F
F
E
E
R
R
980
|
F
F
Q
Q
E
E
M
M
C
C
Y
Y
K
K
A
A
Y
Y
L
L
990
|
A
A
I
I
R
R
Q
Q
H
H
A
A
N
N
L
L
F
F
I
I
1000
|
N
N
L
L
F
F
S
S
M
M
M
M
L
L
G
G
S
S
G
G
1010
|
M
M
P
P
E
E
L
L
Q
Q
S
S
F
F
D
D
D
D
I
I
1020
|
A
A
Y
Y
I
I
R
R
K
K
T
T
L
L
A
A
L
L
D
D
1030
|
K
K
T
T
E
E
Q
Q
E
E
A
A
L
L
E
E
Y
Y
F
F
1040
|
M
M
K
K
Q
Q
M
M
N
N
D
D
A
A
H
R
H
H
G
G
1050
|
G
G
W
W
T
T
T
T
K
K
M
M
D
D
W
W
I
I
F
F
1060
|
H
H
T
T
I
I
K
K
Q
Q
H
H
A
A
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF10A cells Breast Homo sapiens (Human) CVCL_0598
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model Female nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Mechanism Description The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [9]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.L597S (c.1789_1790delCTinsTC)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Melanoma thyroid metastasis N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description The missense mutation p.L597S (c.1789_1790delCTinsTC) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [9]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.L597R (c.1790T>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Melanoma thyroid metastasis N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description The missense mutation p.L597R (c.1790T>G) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [9]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.K601E (c.1801A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Melanoma thyroid metastasis N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description The missense mutation p.K601E (c.1801A>G) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [10]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.F247L (c.739T>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Activation hsa04010
In Vitro Model MCF10A cells Breast Homo sapiens (Human) CVCL_0598
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMLER cells Breast Homo sapiens (Human) CVCL_DG85
In Vivo Model Athymic mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting assay; Immunofluorescence assay; qPCR
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Reseachers identified an oncogenic mutation, F247L, whose expression robustly activated the MAPK pathway and sensitized cells to BRAF and MEK inhibitors.
Key Molecule: Granulocyte colony-stimulating factor receptor (CSF3R) [11]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.N610S (c.1829A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model C57/BL6 mouse model Mus musculus
Experiment for
Molecule Alteration		 Sanger genomic DNA sequencing assay
Experiment for
Drug Resistance		 MTS assay
Key Molecule: Granulocyte colony-stimulating factor receptor (CSF3R) [11]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.N610H (c.1828A>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model C57/BL6 mouse model Mus musculus
Experiment for
Molecule Alteration		 Sanger genomic DNA sequencing assay
Experiment for
Drug Resistance		 MTS assay
Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [12]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.Y288C (c.863A>G)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF10A cells Breast Homo sapiens (Human) CVCL_0598
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Presto blue assay
Mechanism Description PDGFRA Y288C induces constitutive phosphorylation of Akt, ERK1/2, and STAT3. PDGFRA Y288C is resistant to PDGFR inhibitors, such as crenolanib, but sensitive to PI3K/mTOR and MEK inhibitors, such as omipalisib, consistent with pathway activation results.
Key Molecule: PI3-kinase alpha (PIK3CA) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.N345K (c.1035T>G)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF10A cells Breast Homo sapiens (Human) CVCL_0598
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model Female nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Mechanism Description The missense mutation p.N345K (c.1035T>G) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: PI3-kinase alpha (PIK3CA) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.E545K (c.1633G>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF10A cells Breast Homo sapiens (Human) CVCL_0598
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model Female nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Mechanism Description The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: PI3-kinase alpha (PIK3CA) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.Q546K (c.1636C>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF10A cells Breast Homo sapiens (Human) CVCL_0598
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model Female nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Mechanism Description The missense mutation p.Q546K (c.1636C>A) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: PI3-kinase alpha (PIK3CA) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.G1049R (c.3145G>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF10A cells Breast Homo sapiens (Human) CVCL_0598
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model Female nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Mechanism Description The missense mutation p.G1049R (c.3145G>C) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Atypical chronic myeloid leukemia [ICD-11: 2A41]
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: Protein kinase C eta type (PRKCH) [13]
Sensitive Disease Atypical chronic myeloid leukemia [ICD-11: 2A41.1]
 Disease Info 
Molecule Alteration Copy number gain
.
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Human CML cells Peripheral blood Homo sapiens (Human) CVCL_E508
BCR-ABL mouse primary bone marrow cells N.A. Mus musculus (Mouse) N.A.
In Vivo Model Mouse model of BCR-ABL-independent IM-resistant CML Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Colony formation assay
Esophageal cancer [ICD-11: 2B70]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Histone H1.4 (H1-4) [2]
Resistant Disease Oesophagus adenocarcinoma [ICD-11: 2B70.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vivo Model Patient-derived esophageal cancer model Homo sapiens
Experiment for
Molecule Alteration		 Gene expression analysis
Experiment for
Drug Resistance		 Drug sensitivity analysis
Mechanism Description The results of drug sensitivity of risk genes showed that the high expression of HIST1H1E made tumor cells resistant to trametinib, selumetinib, RDEA119, Docetaxel and 17-AAG. The high expression of UBE2C makes tumor cells resistant to masitinib. The low expression of ERO1B makes the EC more sensitive to FK866
Gastric cancer [ICD-11: 2B72]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: MAPK/ERK kinase 1 (MEK1) [7]
Sensitive Disease Gastric adenocarcinoma [ICD-11: 2B72.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q56P (c.167A>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
AGS cells Gastric Homo sapiens (Human) CVCL_0139
NCI-N87 cells Gastric Homo sapiens (Human) CVCL_1603
NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
SW48 cells Colon Homo sapiens (Human) CVCL_1724
A549 cells Lung Homo sapiens (Human) CVCL_0023
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-H1650 cells Lung Homo sapiens (Human) CVCL_1483
SW1573 cells Lung Homo sapiens (Human) CVCL_1720
SNU-C1 cells Peritoneum Homo sapiens (Human) CVCL_1708
OCUM-1 cells Pleural effusion Homo sapiens (Human) CVCL_3084
NCI-H226 cells Pleural effusion Homo sapiens (Human) CVCL_1544
NCI-H196 cells Pleural effusion Homo sapiens (Human) CVCL_1509
NCI-H1437 cells Pleural effusion Homo sapiens (Human) CVCL_1472
NCI-H1355 cells Pleural effusion Homo sapiens (Human) CVCL_1464
MKN7 cells Lymph node Homo sapiens (Human) CVCL_1417
NCI-H1299 cells Lymph node Homo sapiens (Human) CVCL_0060
HCC366 cells Lung Homo sapiens (Human) CVCL_2059
NCI-H2126 cells Pleural effusion Homo sapiens (Human) CVCL_1532
In Vivo Model Female nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay
Colorectal cancer [ICD-11: 2B91]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: MAPK/ERK kinase 1 (MEK1) [7]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Missense mutation
p.F53L (c.157T>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
A549 cells Lung Homo sapiens (Human) CVCL_0023
AGS cells Gastric Homo sapiens (Human) CVCL_0139
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-N87 cells Gastric Homo sapiens (Human) CVCL_1603
NCI-H1650 cells Lung Homo sapiens (Human) CVCL_1483
NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
SW48 cells Colon Homo sapiens (Human) CVCL_1724
SW1573 cells Lung Homo sapiens (Human) CVCL_1720
SNU-C1 cells Peritoneum Homo sapiens (Human) CVCL_1708
OCUM-1 cells Pleural effusion Homo sapiens (Human) CVCL_3084
NCI-H226 cells Pleural effusion Homo sapiens (Human) CVCL_1544
NCI-H196 cells Pleural effusion Homo sapiens (Human) CVCL_1509
NCI-H1437 cells Pleural effusion Homo sapiens (Human) CVCL_1472
NCI-H1355 cells Pleural effusion Homo sapiens (Human) CVCL_1464
NCI-H1299 cells Lymph node Homo sapiens (Human) CVCL_0060
MKN7 cells Lymph node Homo sapiens (Human) CVCL_1417
HCC366 cells Lung Homo sapiens (Human) CVCL_2059
NCI-H2126 cells Pleural effusion Homo sapiens (Human) CVCL_1532
In Vivo Model Female nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [14]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Missense mutation
p.G466V (c.1397G>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation ERK signaling pathway Activation hsa04210
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H1299 cells Lung Homo sapiens (Human) CVCL_0060
HT-29 cells Colon Homo sapiens (Human) CVCL_0320
H1650 cells Pleural effusion Homo sapiens (Human) CVCL_4V01
HTB-56 cells Pleural effusion Homo sapiens (Human) CVCL_0236
HTB-38 cells Colon Homo sapiens (Human) CVCL_0320
HTB-183 cells Lymph node Homo sapiens (Human) CVCL_1577
H661 cells Lymph node Homo sapiens (Human) CVCL_1577
H508 cells Abdominal wall Homo sapiens (Human) CVCL_1564
H2405 cells Lung Homo sapiens (Human) CVCL_1551
H1666 cells Pleural effusion Homo sapiens (Human) CVCL_1485
H1395 cells Lung Homo sapiens (Human) CVCL_1467
CRL-5944 cells Ascites Homo sapiens (Human) CVCL_1551
CRL-5885 cells Pleural effusion Homo sapiens (Human) CVCL_1485
CRL-5883 cells Pleural effusion Homo sapiens (Human) CVCL_1483
CRL-5868 cells Lung Homo sapiens (Human) CVCL_1467
CRL-5803 cells Lymph node Homo sapiens (Human) CVCL_0060
CCL-253 cells Abdominal wall Homo sapiens (Human) CVCL_1564
CCL-185 cells Bowel Homo sapiens (Human) CVCL_0023
Calu-6 cells Lung Homo sapiens (Human) CVCL_0236
In Vivo Model NSG mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Researchers defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [14]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Missense mutation
p.G596R (c.1786G>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation ERK signaling pathway Activation hsa04210
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H1299 cells Lung Homo sapiens (Human) CVCL_0060
HT-29 cells Colon Homo sapiens (Human) CVCL_0320
H1650 cells Pleural effusion Homo sapiens (Human) CVCL_4V01
HTB-56 cells Pleural effusion Homo sapiens (Human) CVCL_0236
HTB-38 cells Colon Homo sapiens (Human) CVCL_0320
HTB-183 cells Lymph node Homo sapiens (Human) CVCL_1577
H661 cells Lymph node Homo sapiens (Human) CVCL_1577
H508 cells Abdominal wall Homo sapiens (Human) CVCL_1564
H2405 cells Lung Homo sapiens (Human) CVCL_1551
H1666 cells Pleural effusion Homo sapiens (Human) CVCL_1485
H1395 cells Lung Homo sapiens (Human) CVCL_1467
CRL-5944 cells Ascites Homo sapiens (Human) CVCL_1551
CRL-5885 cells Pleural effusion Homo sapiens (Human) CVCL_1485
CRL-5883 cells Pleural effusion Homo sapiens (Human) CVCL_1483
CRL-5868 cells Lung Homo sapiens (Human) CVCL_1467
CRL-5803 cells Lymph node Homo sapiens (Human) CVCL_0060
CCL-253 cells Abdominal wall Homo sapiens (Human) CVCL_1564
CCL-185 cells Bowel Homo sapiens (Human) CVCL_0023
Calu-6 cells Lung Homo sapiens (Human) CVCL_0236
In Vivo Model NSG mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Researchers defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.
Pancreatic cancer [ICD-11: 2C10]
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: Serine/threonine-protein kinase B-raf (BRAF) [5]
Resistant Disease Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
 Disease Info 
Molecule Alteration Missense mutation
p.K601E (c.1801A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
A375 cells Skin Homo sapiens (Human) CVCL_0132
NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
NT-3 cells Lymph node Homo sapiens (Human) CVCL_VG81
Experiment for
Drug Resistance		 BioRad TC20 automated cell counter assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [15]
Sensitive Disease Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
 Disease Info 
Molecule Alteration Complex-indel
p.V487_P492delinsA (c.1460_1474del15)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
A375 cells Skin Homo sapiens (Human) CVCL_0132
BxPC-3 cells Pancreas Homo sapiens (Human) CVCL_0186
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
OV-90 cells Ascites Homo sapiens (Human) CVCL_3768
H2405 cells Lung Homo sapiens (Human) CVCL_1551
In Vivo Model NIH nude rat xenograft model Rattus norvegicus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay; Colony transformation assay; Cell-cycle analysis; BrdUrd incorporation assay
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [16]
Sensitive Disease Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
 Disease Info 
Molecule Alteration IF-deletion
p.N486_P490delNVTAP (c.1457_1471del15)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Blood sample N.A.
Lung cancer [ICD-11: 2C25]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: MAPK/ERK kinase 1 (MEK1) [7]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q56P (c.167A>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
AGS cells Gastric Homo sapiens (Human) CVCL_0139
NCI-N87 cells Gastric Homo sapiens (Human) CVCL_1603
NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
SW48 cells Colon Homo sapiens (Human) CVCL_1724
A549 cells Lung Homo sapiens (Human) CVCL_0023
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-H1650 cells Lung Homo sapiens (Human) CVCL_1483
SW1573 cells Lung Homo sapiens (Human) CVCL_1720
SNU-C1 cells Peritoneum Homo sapiens (Human) CVCL_1708
OCUM-1 cells Pleural effusion Homo sapiens (Human) CVCL_3084
NCI-H226 cells Pleural effusion Homo sapiens (Human) CVCL_1544
NCI-H196 cells Pleural effusion Homo sapiens (Human) CVCL_1509
NCI-H1437 cells Pleural effusion Homo sapiens (Human) CVCL_1472
NCI-H1355 cells Pleural effusion Homo sapiens (Human) CVCL_1464
MKN7 cells Lymph node Homo sapiens (Human) CVCL_1417
NCI-H1299 cells Lymph node Homo sapiens (Human) CVCL_0060
HCC366 cells Lung Homo sapiens (Human) CVCL_2059
NCI-H2126 cells Pleural effusion Homo sapiens (Human) CVCL_1532
In Vivo Model Female nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [17]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q61K (c.181C>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.74  Å
PDB: 8VM2
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.75
TM score: 0.98025
Amino acid change:
Q61K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-10
|
-
S
-
S
-
G
-
R
-
E
-
N
-
L
-
Y
-
F
-
Q
0
|
S
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
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
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
K
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
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
S
90
|
F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
H
H
E
E
L
L
A
A
K
K
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
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
K
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model H1299 cells Lung Homo sapiens (Human) CVCL_0060
SW1271 cells Lung Homo sapiens (Human) CVCL_1716
H2347 cells Lung Homo sapiens (Human) CVCL_1550
H2087 cells Lymph node Homo sapiens (Human) CVCL_1524
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Cell Titer blue reagent assay
Mechanism Description The missense mutation p.Q61K (c.181C>A) in gene NRAS cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase A-Raf (ARAF) [18]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Missense mutation
p.S214C (c.641C>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model AALE cells N.A. Aedes albopictus (Asian tiger mosquito) (Stegomyia albopicta) CVCL_Z230
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Soft-agar colony formation assay
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [14]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Missense mutation
p.G466V (c.1397G>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation ERK signaling pathway Activation hsa04210
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H1299 cells Lung Homo sapiens (Human) CVCL_0060
HT-29 cells Colon Homo sapiens (Human) CVCL_0320
H1650 cells Pleural effusion Homo sapiens (Human) CVCL_4V01
HTB-56 cells Pleural effusion Homo sapiens (Human) CVCL_0236
HTB-38 cells Colon Homo sapiens (Human) CVCL_0320
HTB-183 cells Lymph node Homo sapiens (Human) CVCL_1577
H661 cells Lymph node Homo sapiens (Human) CVCL_1577
H508 cells Abdominal wall Homo sapiens (Human) CVCL_1564
H2405 cells Lung Homo sapiens (Human) CVCL_1551
H1666 cells Pleural effusion Homo sapiens (Human) CVCL_1485
H1395 cells Lung Homo sapiens (Human) CVCL_1467
CRL-5944 cells Ascites Homo sapiens (Human) CVCL_1551
CRL-5885 cells Pleural effusion Homo sapiens (Human) CVCL_1485
CRL-5883 cells Pleural effusion Homo sapiens (Human) CVCL_1483
CRL-5868 cells Lung Homo sapiens (Human) CVCL_1467
CRL-5803 cells Lymph node Homo sapiens (Human) CVCL_0060
CCL-253 cells Abdominal wall Homo sapiens (Human) CVCL_1564
CCL-185 cells Bowel Homo sapiens (Human) CVCL_0023
Calu-6 cells Lung Homo sapiens (Human) CVCL_0236
In Vivo Model NSG mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Researchers defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [15]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Complex-indel
p.L485_P490delinsY (c.1453_1470delinsTAT)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
A375 cells Skin Homo sapiens (Human) CVCL_0132
BxPC-3 cells Pancreas Homo sapiens (Human) CVCL_0186
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
OV-90 cells Ascites Homo sapiens (Human) CVCL_3768
H2405 cells Lung Homo sapiens (Human) CVCL_1551
In Vivo Model NIH nude rat xenograft model Rattus norvegicus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay; Colony transformation assay; Cell-cycle analysis; BrdUrd incorporation assay
Key Molecule: Serine/threonine-protein kinase STK11 (STK11) [19]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Nonsense
p.Q37* (c.109C>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MEK signaling pathway Inhibition hsa04011
In Vitro Model H292 cells Lung Homo sapiens (Human) CVCL_0455
H1299 cells Lung Homo sapiens (Human) CVCL_0060
H157 cells Lung Homo sapiens (Human) CVCL_2458
H23 cells Lung Homo sapiens (Human) CVCL_1547
Calu-3 cells Lung Homo sapiens (Human) CVCL_0609
HCC78 cells Pleural effusion Homo sapiens (Human) CVCL_2061
HCC515 cells Lymph node Homo sapiens (Human) CVCL_5136
HCC2935 cells Lung Homo sapiens (Human) CVCL_1265
HCC193 cells Lung Homo sapiens (Human) CVCL_5130
HCC15 cells Lung Homo sapiens (Human) CVCL_2057
H520 cells Lung Homo sapiens (Human) CVCL_1566
H2126 cells Pleural effusion Homo sapiens (Human) CVCL_1532
H2122 cells Pleural effusion Homo sapiens (Human) CVCL_1531
H2085 cells Lung Homo sapiens (Human) CVCL_1523
H1993 cells Lymph node Homo sapiens (Human) CVCL_1512
H1435 cells Lung Homo sapiens (Human) CVCL_1470
H1395 cells Lung Homo sapiens (Human) CVCL_1467
H1355 cells Pleural effusion Homo sapiens (Human) CVCL_1464
Calu-6 cells Lung Homo sapiens (Human) CVCL_0236
Calu-1 cells Lung Homo sapiens (Human) CVCL_0608
In Vivo Model NOD-SCID mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Alamar blue proliferation assay
Key Molecule: Serine/threonine-protein kinase STK11 (STK11) [19]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Nonsense
p.E199* (c.595G>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MEK signaling pathway Inhibition hsa04011
In Vitro Model H292 cells Lung Homo sapiens (Human) CVCL_0455
H1299 cells Lung Homo sapiens (Human) CVCL_0060
H157 cells Lung Homo sapiens (Human) CVCL_2458
H23 cells Lung Homo sapiens (Human) CVCL_1547
Calu-3 cells Lung Homo sapiens (Human) CVCL_0609
HCC78 cells Pleural effusion Homo sapiens (Human) CVCL_2061
HCC515 cells Lymph node Homo sapiens (Human) CVCL_5136
HCC2935 cells Lung Homo sapiens (Human) CVCL_1265
HCC193 cells Lung Homo sapiens (Human) CVCL_5130
HCC15 cells Lung Homo sapiens (Human) CVCL_2057
H520 cells Lung Homo sapiens (Human) CVCL_1566
H2126 cells Pleural effusion Homo sapiens (Human) CVCL_1532
H2122 cells Pleural effusion Homo sapiens (Human) CVCL_1531
H2085 cells Lung Homo sapiens (Human) CVCL_1523
H1993 cells Lymph node Homo sapiens (Human) CVCL_1512
H1435 cells Lung Homo sapiens (Human) CVCL_1470
H1395 cells Lung Homo sapiens (Human) CVCL_1467
H1355 cells Pleural effusion Homo sapiens (Human) CVCL_1464
Calu-6 cells Lung Homo sapiens (Human) CVCL_0236
Calu-1 cells Lung Homo sapiens (Human) CVCL_0608
In Vivo Model NOD-SCID mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Alamar blue proliferation assay
Key Molecule: Serine/threonine-protein kinase STK11 (STK11) [19]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Nonsense
p.W332* (c.995G>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MEK signaling pathway Inhibition hsa04011
In Vitro Model H292 cells Lung Homo sapiens (Human) CVCL_0455
H1299 cells Lung Homo sapiens (Human) CVCL_0060
H157 cells Lung Homo sapiens (Human) CVCL_2458
H23 cells Lung Homo sapiens (Human) CVCL_1547
Calu-3 cells Lung Homo sapiens (Human) CVCL_0609
HCC78 cells Pleural effusion Homo sapiens (Human) CVCL_2061
HCC515 cells Lymph node Homo sapiens (Human) CVCL_5136
HCC2935 cells Lung Homo sapiens (Human) CVCL_1265
HCC193 cells Lung Homo sapiens (Human) CVCL_5130
HCC15 cells Lung Homo sapiens (Human) CVCL_2057
H520 cells Lung Homo sapiens (Human) CVCL_1566
H2126 cells Pleural effusion Homo sapiens (Human) CVCL_1532
H2122 cells Pleural effusion Homo sapiens (Human) CVCL_1531
H2085 cells Lung Homo sapiens (Human) CVCL_1523
H1993 cells Lymph node Homo sapiens (Human) CVCL_1512
H1435 cells Lung Homo sapiens (Human) CVCL_1470
H1395 cells Lung Homo sapiens (Human) CVCL_1467
H1355 cells Pleural effusion Homo sapiens (Human) CVCL_1464
Calu-6 cells Lung Homo sapiens (Human) CVCL_0236
Calu-1 cells Lung Homo sapiens (Human) CVCL_0608
In Vivo Model NOD-SCID mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Alamar blue proliferation assay
Melanoma [ICD-11: 2C30]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.V60E (c.179T>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
A2058 cells Skin Homo sapiens (Human) CVCL_1059
WM2664 cells Skin Homo sapiens (Human) CVCL_2765
SkMEL28 cells Skin Homo sapiens (Human) CVCL_0526
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [20]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.L597Q (c.1790T>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [9]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.K601E (c.1801A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Melanoma thyroid metastasis N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description The missense mutation p.K601E (c.1801A>G) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [21]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.K601E (c.1801A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [21]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.L597R (c.1790T>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Whole-gene resequencing assay
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [21]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.V600R (c.1798_1799delGTinsAG)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [22]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.L597V (c.1789C>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Skin N.A.
Experiment for
Molecule Alteration		 Tumour genotyping assay
Mechanism Description The missense mutation p.L597V (c.1789C>G) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [9]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.L597S (c.1789_1790delCTinsTC)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Melanoma thyroid metastasis N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description The missense mutation p.L597S (c.1789_1790delCTinsTC) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [14]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.D594G (c.1781A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation ERK signaling pathway Activation hsa04210
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H1299 cells Lung Homo sapiens (Human) CVCL_0060
HT-29 cells Colon Homo sapiens (Human) CVCL_0320
H1650 cells Pleural effusion Homo sapiens (Human) CVCL_4V01
HTB-56 cells Pleural effusion Homo sapiens (Human) CVCL_0236
HTB-38 cells Colon Homo sapiens (Human) CVCL_0320
HTB-183 cells Lymph node Homo sapiens (Human) CVCL_1577
H661 cells Lymph node Homo sapiens (Human) CVCL_1577
H508 cells Abdominal wall Homo sapiens (Human) CVCL_1564
H2405 cells Lung Homo sapiens (Human) CVCL_1551
H1666 cells Pleural effusion Homo sapiens (Human) CVCL_1485
H1395 cells Lung Homo sapiens (Human) CVCL_1467
CRL-5944 cells Ascites Homo sapiens (Human) CVCL_1551
CRL-5885 cells Pleural effusion Homo sapiens (Human) CVCL_1485
CRL-5883 cells Pleural effusion Homo sapiens (Human) CVCL_1483
CRL-5868 cells Lung Homo sapiens (Human) CVCL_1467
CRL-5803 cells Lymph node Homo sapiens (Human) CVCL_0060
CCL-253 cells Abdominal wall Homo sapiens (Human) CVCL_1564
CCL-185 cells Bowel Homo sapiens (Human) CVCL_0023
Calu-6 cells Lung Homo sapiens (Human) CVCL_0236
In Vivo Model NSG mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Researchers defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [23]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.L597S (c.1789_1790delCTinsTC)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
In Vitro Model Skin sample N.A.
In Vivo Model Mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Crystal violet staining assay
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [24]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.D594V (c.1781A>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Experiment for
Molecule Alteration		 Immunoblotting analysis
Mechanism Description The missense mutation p.D594V (c.1781A>T) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [25]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Synonymous
p.K601K (c.1803A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [23]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Synonymous
p.L597L (c.1791A>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [21]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.K601R (c.1802A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [22]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.L597R (c.1790T>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293H cells Fetal kidney Homo sapiens (Human) CVCL_ZK99
Experiment for
Molecule Alteration		 Whole genome sequencing assay
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [26]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.V600K (c.1798_1799delGTinsAA)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Breast cancer [ICD-11: 2C60]
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: PI3-kinase alpha (PIK3CA) [8]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Missense mutation
p.H1047R (c.3140A>G)
 Molecule Info 
Wild Type Structure Method: Electron microscopy Resolution: 2.41  Å
PDB: 8DCP
Mutant Type Structure Method: X-ray diffraction Resolution: 2.61  Å
PDB: 8V8V
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.09
TM score: 0.95656
Amino acid change:
H1047R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
-
S
-
Y
-
Y
-
H
-
H
-
H
-
-20
|
H
-
H
-
H
-
D
-
Y
-
D
-
I
-
P
-
T
-
T
-
-10
|
E
-
N
-
L
-
Y
-
F
-
Q
-
G
G
A
A
M
M
G
G
0
|
S
S
M
M
P
P
P
P
R
R
P
P
S
S
S
S
G
G
E
E
10
|
L
L
W
W
G
G
I
I
H
H
L
L
M
M
P
P
P
P
R
R
20
|
I
I
L
L
V
V
E
E
C
C
L
L
L
L
P
P
N
N
G
G
30
|
M
M
I
I
V
V
T
T
L
L
E
E
C
C
L
L
R
R
E
E
40
|
A
A
T
T
L
L
I
I
T
T
I
I
K
K
H
H
E
E
L
L
50
|
F
F
K
K
E
E
A
A
R
R
K
K
Y
Y
P
P
L
L
H
H
60
|
Q
Q
L
L
L
L
Q
Q
D
D
E
E
S
S
S
S
Y
Y
I
I
70
|
F
F
V
V
S
S
V
V
T
T
Q
Q
E
E
A
A
E
E
R
R
80
|
E
E
E
E
F
F
F
F
D
D
E
E
T
T
R
R
R
R
L
L
90
|
C
C
D
D
L
L
R
R
L
L
F
F
Q
Q
P
P
F
F
L
L
100
|
K
K
V
V
I
I
E
E
P
P
V
V
G
G
N
N
R
R
E
E
110
|
E
E
K
K
I
I
L
L
N
N
R
R
E
E
I
I
G
G
F
F
120
|
A
A
I
I
G
G
M
M
P
P
V
V
C
C
E
E
F
F
D
D
130
|
M
M
V
V
K
K
D
D
P
P
E
E
V
V
Q
Q
D
D
F
F
140
|
R
R
R
R
N
N
I
I
L
L
N
N
V
V
C
C
K
K
E
E
150
|
A
A
V
V
D
D
L
L
R
R
D
D
L
L
N
N
S
S
P
P
160
|
H
H
S
S
R
R
A
A
M
M
Y
Y
V
V
Y
Y
P
P
P
P
170
|
N
N
V
V
E
E
S
S
S
S
P
P
E
E
L
L
P
P
K
K
180
|
H
H
I
I
Y
Y
N
N
K
K
L
L
D
D
K
K
G
G
Q
Q
190
|
I
I
I
I
V
V
V
V
I
I
W
W
V
V
I
I
V
V
S
S
200
|
P
P
N
N
N
N
D
D
K
K
Q
Q
K
K
Y
Y
T
T
L
L
210
|
K
K
I
I
N
N
H
H
D
D
C
C
V
V
P
P
E
E
Q
Q
220
|
V
V
I
I
A
A
E
E
A
A
I
I
R
R
K
K
K
K
T
T
230
|
R
R
S
S
M
M
L
L
L
L
S
S
S
S
E
E
Q
Q
L
L
240
|
K
K
L
L
C
C
V
V
L
L
E
E
Y
Y
Q
Q
G
G
K
K
250
|
Y
Y
I
I
L
L
K
K
V
V
C
C
G
G
C
C
D
D
E
E
260
|
Y
Y
F
F
L
L
E
E
K
K
Y
Y
P
P
L
L
S
S
Q
Q
270
|
Y
Y
K
K
Y
Y
I
I
R
R
S
S
C
C
I
I
M
M
L
L
280
|
G
G
R
R
M
M
P
P
N
N
L
L
M
M
L
L
M
M
A
A
290
|
K
K
E
E
S
S
L
L
Y
Y
S
S
Q
Q
L
L
P
P
M
M
300
|
D
D
C
C
F
F
T
T
M
M
P
P
S
S
Y
Y
S
S
R
R
310
|
R
R
I
I
S
S
T
T
A
A
T
T
P
P
Y
Y
M
M
N
N
320
|
G
G
E
E
T
T
S
S
T
T
K
K
S
S
L
L
W
W
V
V
330
|
I
I
N
N
S
S
A
A
L
L
R
R
I
I
K
K
I
I
L
L
340
|
C
C
A
A
T
T
Y
Y
V
V
N
N
V
V
N
N
I
I
R
R
350
|
D
D
I
I
D
D
K
K
I
I
Y
Y
V
V
R
R
T
T
G
G
360
|
I
I
Y
Y
H
H
G
G
G
G
E
E
P
P
L
L
C
C
D
D
370
|
N
N
V
V
N
N
T
T
Q
Q
R
R
V
V
P
P
C
C
S
S
380
|
N
N
P
P
R
R
W
W
N
N
E
E
W
W
L
L
N
N
Y
Y
390
|
D
D
I
I
Y
Y
I
I
P
P
D
D
L
L
P
P
R
R
A
A
400
|
A
A
R
R
L
L
C
C
L
L
S
S
I
I
C
C
S
S
V
V
410
|
K
K
G
G
R
R
K
K
G
G
A
A
K
K
E
E
E
E
H
H
420
|
C
C
P
P
L
L
A
A
W
W
G
G
N
N
I
I
N
N
L
L
430
|
F
F
D
D
Y
Y
T
T
D
D
T
T
L
L
V
V
S
S
G
G
440
|
K
K
M
M
A
A
L
L
N
N
L
L
W
W
P
P
V
V
P
P
450
|
H
H
G
G
L
L
E
E
D
D
L
L
L
L
N
N
P
P
I
I
460
|
G
G
V
V
T
T
G
G
S
S
N
N
P
P
N
N
K
K
E
E
470
|
T
T
P
P
C
C
L
L
E
E
L
L
E
E
F
F
D
D
W
W
480
|
F
F
S
S
S
S
V
V
V
V
K
K
F
F
P
P
D
D
M
M
490
|
S
S
V
V
I
I
E
E
E
E
H
H
A
A
N
N
W
W
S
S
500
|
V
V
S
S
R
R
E
E
A
A
G
G
F
F
S
S
Y
Y
S
S
510
|
H
H
A
A
G
G
L
L
S
S
N
N
R
R
L
L
A
A
R
R
520
|
D
D
N
N
E
E
L
L
R
R
E
E
N
N
D
D
K
K
E
E
530
|
Q
Q
L
L
K
K
A
A
I
I
S
S
T
T
R
R
D
D
P
P
540
|
L
L
S
S
E
E
I
I
T
T
E
E
Q
Q
E
E
K
K
D
D
550
|
F
F
L
L
W
W
S
S
H
H
R
R
H
H
Y
Y
C
C
V
V
560
|
T
T
I
I
P
P
E
E
I
I
L
L
P
P
K
K
L
L
L
L
570
|
L
L
S
S
V
V
K
K
W
W
N
N
S
S
R
R
D
D
E
E
580
|
V
V
A
A
Q
Q
M
M
Y
Y
C
C
L
L
V
V
K
K
D
D
590
|
W
W
P
P
P
P
I
I
K
K
P
P
E
E
Q
Q
A
A
M
M
600
|
E
E
L
L
L
L
D
D
C
C
N
N
Y
Y
P
P
D
D
P
P
610
|
M
M
V
V
R
R
G
G
F
F
A
A
V
V
R
R
C
C
L
L
620
|
E
E
K
K
Y
Y
L
L
T
T
D
D
D
D
K
K
L
L
S
S
630
|
Q
Q
Y
Y
L
L
I
I
Q
Q
L
L
V
V
Q
Q
V
V
L
L
640
|
K
K
Y
Y
E
E
Q
Q
Y
Y
L
L
D
D
N
N
L
L
L
L
650
|
V
V
R
R
F
F
L
L
L
L
K
K
K
K
A
A
L
L
T
T
660
|
N
N
Q
Q
R
R
I
I
G
G
H
H
F
F
F
F
F
F
W
W
670
|
H
H
L
L
K
K
S
S
E
E
M
M
H
H
N
N
K
K
T
T
680
|
V
V
S
S
Q
Q
R
R
F
F
G
G
L
L
L
L
L
L
E
E
690
|
S
S
Y
Y
C
C
R
R
A
A
C
C
G
G
M
M
Y
Y
L
L
700
|
K
K
H
H
L
L
N
N
R
R
Q
Q
V
V
E
E
A
A
M
M
710
|
E
E
K
K
L
L
I
I
N
N
L
L
T
T
D
D
I
I
L
L
720
|
K
K
Q
Q
E
E
K
K
K
K
D
D
E
E
T
T
Q
Q
K
K
730
|
V
V
Q
Q
M
M
K
K
F
F
L
L
V
V
E
E
Q
Q
M
M
740
|
R
R
R
R
P
P
D
D
F
F
M
M
D
D
A
A
L
L
Q
Q
750
|
G
G
F
F
L
L
S
S
P
P
L
L
N
N
P
P
A
A
H
H
760
|
Q
Q
L
L
G
G
N
N
L
L
R
R
L
L
E
E
E
E
C
C
770
|
R
R
I
I
M
M
S
S
S
S
A
A
K
K
R
R
P
P
L
L
780
|
W
W
L
L
N
N
W
W
E
E
N
N
P
P
D
D
I
I
M
M
790
|
S
S
E
E
L
L
L
L
F
F
Q
Q
N
N
N
N
E
E
I
I
800
|
I
I
F
F
K
K
N
N
G
G
D
D
D
D
L
L
R
R
Q
Q
810
|
D
D
M
M
L
L
T
T
L
L
Q
Q
I
I
I
I
R
R
I
I
820
|
M
M
E
E
N
N
I
I
W
W
Q
Q
N
N
Q
Q
G
G
L
L
830
|
D
D
L
L
R
R
M
M
L
L
P
P
Y
Y
G
G
C
C
L
L
840
|
S
S
I
I
G
G
D
D
C
C
V
V
G
G
L
L
I
I
E
E
850
|
V
V
V
V
R
R
N
N
S
S
H
H
T
T
I
I
M
M
Q
Q
860
|
I
I
Q
Q
C
C
K
K
G
G
G
G
L
L
K
K
G
G
A
A
870
|
L
L
Q
Q
F
F
N
N
S
S
H
H
T
T
L
L
H
H
Q
Q
880
|
W
W
L
L
K
K
D
D
K
K
N
N
K
K
G
G
E
E
I
I
890
|
Y
Y
D
D
A
A
A
A
I
I
D
D
L
L
F
F
T
T
R
R
900
|
S
S
C
C
A
A
G
G
Y
Y
C
C
V
V
A
A
T
T
F
F
910
|
I
I
L
L
G
G
I
I
G
G
D
D
R
R
H
H
N
N
S
S
920
|
N
N
I
I
M
M
V
V
K
K
D
D
D
D
G
G
Q
Q
L
L
930
|
F
F
H
H
I
I
D
D
F
F
G
G
H
H
F
F
L
L
D
D
940
|
H
H
K
K
K
K
K
K
K
K
F
F
G
G
Y
Y
K
K
R
R
950
|
E
E
R
R
V
V
P
P
F
F
V
V
L
L
T
T
Q
Q
D
D
960
|
F
F
L
L
I
I
V
V
I
I
S
S
K
K
G
G
A
A
Q
Q
970
|
E
E
C
C
T
T
K
K
T
T
R
R
E
E
F
F
E
E
R
R
980
|
F
F
Q
Q
E
E
M
M
C
C
Y
Y
K
K
A
A
Y
Y
L
L
990
|
A
A
I
I
R
R
Q
Q
H
H
A
A
N
N
L
L
F
F
I
I
1000
|
N
N
L
L
F
F
S
S
M
M
M
M
L
L
G
G
S
S
G
G
1010
|
M
M
P
P
E
E
L
L
Q
Q
S
S
F
F
D
D
D
D
I
I
1020
|
A
A
Y
Y
I
I
R
R
K
K
T
T
L
L
A
A
L
L
D
D
1030
|
K
K
T
T
E
E
Q
Q
E
E
A
A
L
L
E
E
Y
Y
F
F
1040
|
M
M
K
K
Q
Q
M
M
N
N
D
D
A
A
H
R
H
H
G
G
1050
|
G
G
W
W
T
T
T
T
K
K
M
M
D
D
W
W
I
I
F
F
1060
|
H
H
T
T
I
I
K
K
Q
Q
H
H
A
A
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF10A cells Breast Homo sapiens (Human) CVCL_0598
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model Female nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Mechanism Description The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: PI3-kinase alpha (PIK3CA) [8]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Missense mutation
p.H1047L (c.3140A>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.77  Å
PDB: 9ASF
Mutant Type Structure Method: X-ray diffraction Resolution: 1.96  Å
PDB: 7L1C
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.51
TM score: 0.61892
Amino acid change:
H1047L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
A
A
H
L
H
H
G
G
1050
|
G
G
-
W
T
T
T
T
K
K
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF10A cells Breast Homo sapiens (Human) CVCL_0598
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model Female nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Mechanism Description The missense mutation p.H1047L (c.3140A>T) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: PI3-kinase alpha (PIK3CA) [8]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Missense mutation
p.N345K (c.1035T>G)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF10A cells Breast Homo sapiens (Human) CVCL_0598
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model Female nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Mechanism Description The missense mutation p.N345K (c.1035T>G) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: PI3-kinase alpha (PIK3CA) [8]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Missense mutation
p.E542K (c.1624G>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF10A cells Breast Homo sapiens (Human) CVCL_0598
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model Female nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Mechanism Description The missense mutation p.E542K (c.1624G>A) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: PI3-kinase alpha (PIK3CA) [8]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Missense mutation
p.E545K (c.1633G>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF10A cells Breast Homo sapiens (Human) CVCL_0598
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model Female nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Mechanism Description The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: PI3-kinase alpha (PIK3CA) [8]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Missense mutation
p.Q546K (c.1636C>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF10A cells Breast Homo sapiens (Human) CVCL_0598
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model Female nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Mechanism Description The missense mutation p.Q546K (c.1636C>A) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: PI3-kinase alpha (PIK3CA) [8]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Missense mutation
p.G1049R (c.3145G>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF10A cells Breast Homo sapiens (Human) CVCL_0598
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model Female nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Mechanism Description The missense mutation p.G1049R (c.3145G>C) in gene PIK3CA cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [27]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF7 cells Breast Homo sapiens (Human) CVCL_0031
Experiment for
Molecule Alteration		 Immunoblotting assay
Experiment for
Drug Resistance		 Cell cycle assay; Tissue microarrays staining assay
Mechanism Description MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK-733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance.
Ovarian cancer [ICD-11: 2C73]
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: Serine/threonine-protein kinase B-raf (BRAF) [15]
Sensitive Disease Ovarian cancer [ICD-11: 2C73.0]
 Disease Info 
Molecule Alteration IF-deletion
p.N486_P490delNVTAP (c.1457_1471del15)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
A375 cells Skin Homo sapiens (Human) CVCL_0132
BxPC-3 cells Pancreas Homo sapiens (Human) CVCL_0186
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
OV-90 cells Ascites Homo sapiens (Human) CVCL_3768
H2405 cells Lung Homo sapiens (Human) CVCL_1551
In Vivo Model NIH nude rat xenograft model Rattus norvegicus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay; Colony transformation assay; Cell-cycle analysis; BrdUrd incorporation assay
Bladder cancer [ICD-11: 2C94]
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: Serine/threonine-protein kinase B-raf (BRAF) [28]
Sensitive Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Molecule Alteration Other
.
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Uveal melanoma [ICD-11: 2D0Y]
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: Guanine nucleotide-binding protein subunit alpha-11 (GNA11) [29]
Sensitive Disease Uveal melanoma [ICD-11: 2D0Y.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q209L (c.626A>T)
 Molecule Info 
Wild Type Structure Method: Electron microscopy Resolution: 3.50  Å
PDB: 6VU5
Mutant Type Structure Method: Electron microscopy Resolution: 2.90  Å
PDB: 7F6G
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.91
TM score: 0.72705
Amino acid change:
Q209L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-
H
-
H
0
|
-
H
M
H
T
T
L
L
E
E
S
S
I
I
M
M
A
A
C
C
10
|
C
C
L
L
S
S
E
E
E
E
A
A
K
K
E
E
A
A
R
R
20
|
R
R
I
I
N
N
D
D
E
E
I
I
E
E
R
R
Q
Q
L
L
30
|
R
R
R
R
D
D
K
K
R
R
D
D
A
A
R
R
R
R
E
E
40
|
L
L
K
K
L
L
L
L
L
L
L
L
G
G
T
T
G
G
E
E
50
|
S
S
G
G
K
K
S
S
T
T
F
F
I
I
K
K
Q
Q
M
M
60
|
R
R
I
I
I
I
H
H
G
G
S
S
G
G
Y
Y
S
S
D
D
70
|
E
E
D
D
K
K
R
R
G
G
F
F
T
T
K
K
L
L
V
V
80
|
Y
Y
Q
Q
N
N
I
I
F
F
T
T
A
A
M
M
Q
Q
A
A
90
|
M
M
I
I
R
R
A
A
M
M
D
D
T
T
L
L
K
K
I
I
100
|
P
P
Y
Y
K
K
Y
Y
E
E
H
H
N
N
K
K
A
A
H
H
110
|
A
A
Q
Q
L
L
V
V
R
R
E
E
V
V
D
D
V
V
E
E
120
|
K
K
V
V
S
S
A
A
F
F
E
E
N
N
P
P
Y
Y
V
V
130
|
D
D
A
A
I
I
K
K
S
S
L
L
W
W
N
N
D
D
P
P
140
|
G
G
I
I
Q
Q
E
E
C
C
Y
Y
D
D
R
R
R
R
R
R
150
|
E
E
Y
Y
Q
Q
L
L
S
S
D
D
S
S
T
T
K
K
Y
Y
160
|
Y
Y
L
L
N
N
D
D
L
L
D
D
R
R
V
V
A
A
D
D
170
|
P
P
A
A
Y
Y
L
L
P
P
T
T
Q
Q
Q
Q
D
D
V
V
180
|
L
L
R
R
V
V
R
Q
V
V
P
P
T
T
T
T
G
G
I
I
190
|
I
I
E
E
Y
Y
P
P
F
F
D
D
L
L
Q
Q
S
S
V
V
200
|
I
I
F
F
R
R
M
M
V
V
D
D
V
V
G
G
G
G
Q
L
210
|
R
R
S
S
E
E
R
R
R
R
K
K
W
W
I
I
H
H
C
C
220
|
F
F
E
E
N
N
V
V
T
T
S
S
I
I
M
M
F
F
L
L
230
|
V
V
A
A
L
L
S
S
E
E
Y
Y
D
D
Q
Q
V
V
L
L
240
|
V
V
E
E
S
S
D
D
N
N
E
E
N
N
R
R
M
M
E
E
250
|
E
E
S
S
K
K
A
A
L
L
F
F
R
R
T
T
I
I
I
I
260
|
T
T
Y
Y
P
P
W
W
F
F
Q
Q
N
N
S
S
S
S
V
V
270
|
I
I
L
L
F
F
L
L
N
N
K
K
K
K
D
D
L
L
L
L
280
|
E
E
E
E
K
K
I
I
M
M
Y
Y
S
S
H
H
L
L
V
V
290
|
D
D
Y
Y
F
F
P
P
E
E
Y
Y
D
D
G
G
P
P
Q
Q
300
|
R
R
D
D
A
A
Q
Q
A
A
A
A
R
R
E
E
F
F
I
I
310
|
L
L
K
K
M
M
F
F
V
V
D
D
L
L
N
N
P
P
D
D
320
|
S
S
D
D
K
K
I
I
I
I
Y
Y
S
S
H
H
F
F
T
T
330
|
C
C
A
A
T
T
D
D
T
T
E
E
N
N
I
I
R
R
F
F
340
|
V
V
F
F
A
A
A
A
V
V
K
K
D
D
T
T
I
I
L
L
350
|
Q
Q
L
L
N
N
L
L
K
K
E
E
Y
Y
N
N
L
L
V
V
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Cell Titer-blue assay
Mechanism Description The missense mutation p.Q209L (c.626A>T) in gene GNA11 cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Lymphatic system cancer [ICD-11: 2E81]
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: MAPK/ERK kinase 1 (MEK1) [30]
Sensitive Disease Lymphatic system cancer [ICD-11: 2E81.1]
 Disease Info 
Molecule Alteration Missense mutation
p.K57N (c.171G>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Skin N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay
References
Ref 1 Yap1 Mediates Trametinib Resistance in Head and Neck Squamous Cell Carcinomas .Clin Cancer Res. 2021 Apr 15;27(8):2326-2339. doi: 10.1158/1078-0432.CCR-19-4179. Epub 2021 Feb 5. 10.1158/1078-0432.CCR-19-4179
Ref 2 Establishment of prognostic risk model and drug sensitivity based on prognostic related genes of esophageal cancer. Sci Rep. 2022 May 14;12(1):8008.
Ref 3 The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014 Jan;4(1):94-109. doi: 10.1158/2159-8290.CD-13-0617. Epub 2013 Nov 21.
Ref 4 Preclinical assessment of MEK1/2 inhibitors for neurofibromatosis type 2-associated schwannomas reveals differences in efficacy and drug resistance developmentNeuro Oncol. 2019 Mar 18;21(4):486-497. doi: 10.1093/neuonc/noz002.
Ref 5 Rare BRAF mutations in pancreatic neuroendocrine tumors may predict response to RAF and MEK inhibitionPLoS One. 2019 Jun 3;14(6):e0217399. doi: 10.1371/journal.pone.0217399. eCollection 2019.
Ref 6 Regulation of TORC1 by MAPK Signaling Determines Sensitivity and Acquired Resistance to Trametinib in Pediatric BRAFV600E Brain Tumor Models. Clin Cancer Res. 2022 Sep 1;28(17):3836-3849.
Ref 7 Identification of an "Exceptional Responder" Cell Line to MEK1 Inhibition: Clinical Implications for MEK-Targeted TherapyMol Cancer Res. 2016 Feb;14(2):207-15. doi: 10.1158/1541-7786.MCR-15-0321. Epub 2015 Nov 18.
Ref 8 Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare MutationsCancer Res. 2015 Dec 15;75(24):5341-54. doi: 10.1158/0008-5472.CAN-15-1654. Epub 2015 Dec 1.
Ref 9 BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitorsCancer Discov. 2012 Sep;2(9):791-7. doi: 10.1158/2159-8290.CD-12-0097. Epub 2012 Jul 13.
Ref 10 Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of CancerCancer Res. 2017 Jul 1;77(13):3502-3512. doi: 10.1158/0008-5472.CAN-16-2745. Epub 2017 May 16.
Ref 11 A Novel Germline Variant in CSF3R Reduces N-Glycosylation and Exerts Potent Oncogenic Effects in LeukemiaCancer Res. 2018 Dec 15;78(24):6762-6770. doi: 10.1158/0008-5472.CAN-18-1638. Epub 2018 Oct 22.
Ref 12 Neomorphic PDGFRA extracellular domain driver mutations are resistant to PDGFRA targeted therapiesNat Commun. 2018 Nov 2;9(1):4583. doi: 10.1038/s41467-018-06949-w.
Ref 13 A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemiaSci Transl Med. 2014 Sep 3;6(252):252ra121. doi: 10.1126/scitranslmed.3009073.
Ref 14 Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RASNature. 2017 Aug 10;548(7666):234-238. doi: 10.1038/nature23291. Epub 2017 Aug 2.
Ref 15 Oncogenic BRAF Deletions That Function as Homodimers and Are Sensitive to Inhibition by RAF Dimer Inhibitor LY3009120Cancer Discov. 2016 Mar;6(3):300-15. doi: 10.1158/2159-8290.CD-15-0896. Epub 2016 Jan 5.
Ref 16 Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision MedicineCancer Discov. 2018 Sep;8(9):1096-1111. doi: 10.1158/2159-8290.CD-18-0275. Epub 2018 Jun 14.
Ref 17 Characteristics of lung cancers harboring NRAS mutationsClin Cancer Res. 2013 May 1;19(9):2584-91. doi: 10.1158/1078-0432.CCR-12-3173. Epub 2013 Mar 20.
Ref 18 Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinomaJ Clin Invest. 2014 Apr;124(4):1582-6. doi: 10.1172/JCI72763. Epub 2014 Feb 24.
Ref 19 A Transcriptional Signature Identifies LKB1 Functional Status as a Novel Determinant of MEK Sensitivity in Lung AdenocarcinomaCancer Res. 2017 Jan 1;77(1):153-163. doi: 10.1158/0008-5472.CAN-16-1639. Epub 2016 Nov 7.
Ref 20 Activity of trametinib in K601E and L597Q BRAF mutation-positive metastatic melanomaMelanoma Res. 2014 Oct;24(5):504-8. doi: 10.1097/CMR.0000000000000099.
Ref 21 Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitorJ Clin Oncol. 2013 Feb 1;31(4):482-9. doi: 10.1200/JCO.2012.43.5966. Epub 2012 Dec 17.
Ref 22 Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trialLancet Oncol. 2012 Aug;13(8):782-9. doi: 10.1016/S1470-2045(12)70269-3. Epub 2012 Jul 16.
Ref 23 Dual MAPK Inhibition Is an Effective Therapeutic Strategy for a Subset of Class II BRAF Mutant MelanomasClin Cancer Res. 2018 Dec 15;24(24):6483-6494. doi: 10.1158/1078-0432.CCR-17-3384. Epub 2018 Jun 14.
Ref 24 Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAFCell. 2010 Jan 22;140(2):209-21. doi: 10.1016/j.cell.2009.12.040.
Ref 25 Metastatic BRAF K601E-mutated melanoma reaches complete response to MEK inhibitor trametinib administered for over 36 monthsExp Hematol Oncol. 2017 Mar 21;6:6. doi: 10.1186/s40164-017-0067-4. eCollection 2017.
Ref 26 Improved survival with MEK inhibition in BRAF-mutated melanomaN Engl J Med. 2012 Jul 12;367(2):107-14. doi: 10.1056/NEJMoa1203421. Epub 2012 Jun 4.
Ref 27 A kinase inhibitor screen reveals MEK1/2 as a novel therapeutic target to antagonize IGF1R-mediated antiestrogen resistance in ERalpha-positive luminal breast cancer. Biochem Pharmacol. 2022 Oct;204:115233.
Ref 28 Urothelial carcinoma with an NRF1-BRAF rearrangement and response to targeted therapyCold Spring Harb Mol Case Stud. 2019 Jun 3;5(3):a003848. doi: 10.1101/mcs.a003848. Print 2019 Jun.
Ref 29 Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ- and GNA11-dependent mannerClin Cancer Res. 2012 Aug 15;18(16):4345-55. doi: 10.1158/1078-0432.CCR-11-3227. Epub 2012 Jun 25.
Ref 30 Diverse and Targetable Kinase Alterations Drive Histiocytic NeoplasmsCancer Discov. 2016 Feb;6(2):154-65. doi: 10.1158/2159-8290.CD-15-0913. Epub 2015 Nov 13.

If you find any error in data or bug in web service, please kindly report it to Dr. Sun and Dr. Yu.