Drug Information

Drug (ID: DG00304) and It's Reported Resistant Information
Name
Pemetrexed
Synonyms
Alimta; LYA; LY 231514; LY231514; Alimta (TN); LY 231,514; LY-2315; LY-231514; Pemetrexed (INN); Pemetrexed [INN:BAN]; LY-231,514; N-(4-(2-(2-Amino-3,4-dihydro-4-oxo-7H-pyrrolo(2,3-d)pyrimdin-5-yl)ethyl)benzoyl)glutamic acid; N-{4-[2-(2-amino-4-oxo-4,7-dihydro-1h-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-d-glutamic acid; (2R)-2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioic acid; (2S)-2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioic acid; 2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioic acid; 2-{4-[2-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-ETHYL]-BENZOYLAMINO}-PENTANEDIOIC ACID
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Indication
In total 1 Indication(s)
Pleural mesothelioma [ICD-11: 2C26]
Approved
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
Lung cancer [ICD-11: 2C25]
[2]
Pleural mesothelioma [ICD-11: 2C26]
[3]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Lung cancer [ICD-11: 2C25]
[4]
Target Candida Thymidylate synthase (Candi TMP1) TYSY_CANAL [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C20H21N5O6
IsoSMILES
C1=CC(=CC=C1CCC2=CNC3=C2C(=O)NC(=N3)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O
InChI
1S/C20H21N5O6/c21-20-24-16-15(18(29)25-20)12(9-22-16)6-3-10-1-4-11(5-2-10)17(28)23-13(19(30)31)7-8-14(26)27/h1-2,4-5,9,13H,3,6-8H2,(H,23,28)(H,26,27)(H,30,31)(H4,21,22,24,25,29)/t13-/m0/s1
InChIKey
WBXPDJSOTKVWSJ-ZDUSSCGKSA-N
PubChem CID
135410875
ChEBI ID
CHEBI:63616
TTD Drug ID
D0Y4GO
VARIDT ID
DR00318
DrugBank ID
DB00642
Type(s) of Resistant Mechanism of This Drug
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  MRAP: Metabolic Reprogramming via Altered Pathways
  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 Resistance Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Lipocalin-2 (LCN2) [4]
Metabolic Type Glucose metabolism
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Lung cancer [ICD-11: 2C25]
The Specified Disease Lung adenocarcinoma
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.84E-07
Fold-change: 2.07E-01
Z-score: 5.32E+00
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
A549/KL-1 cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description he results of the present study suggested that there may be a new mechanism of action for the antitumor effects of pemetrexed, namely, LCN2-mediated modulation of N-cadherin expression.
Key Molecule: Aldo-keto reductase family 1 member B10 (AKR1B10) [5]
Metabolic Type Glucose metabolism
Resistant Disease Lung cancer brain metastasis [ICD-11: 2C25.3]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Lung cancer [ICD-11: 2C25]
The Specified Disease Lung cancer brain metastasis
The Studied Tissue Lung tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.92E-01
Fold-change: 2.98E-01
Z-score: 1.31E+00
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Highly brain metastatic lung cancer PC9-BrM3 cells Lung Homo sapiens (Human) CVCL_XA19
Experiment for
Drug Resistance		 Cell viability assay; Cell colony formation assay
Mechanism Description Metabolic profiling revealed that AKR1B10 prominently facilitated the Warburg metabolism characterized by the overproduction of lactate. Glycolysis regulated by AKR1B10 is vital for the resistance to PEM. In mechanism, AKR1B10 promoted glycolysis by regulating the expression of lactate dehydrogenase (LDHA) and the increased lactate, acts as a precursor that stimulates histone lactylation (H4K12la), activated the transcription of CCNB1 and accelerated the DNA replication and cell cycle.
Key Molecule: Family with sequence similarity 83 member B (FAM83B) [6]
Metabolic Type Mitochondrial metabolism
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Lung cancer [ICD-11: 2C25]
The Specified Disease Lung adenocarcinoma
The Studied Tissue Lung tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 3.89E-39
Fold-change: 1.68E+00
Z-score: 1.75E+01
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H1299 cells Lung Homo sapiens (Human) CVCL_0060
PC-9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description The mechanistic analysis demonstrated that FAM83B impedes the translocation of calbindin 2 (CALB2) from the cytoplasm to the mitochondria, resulting in the inhibition of apoptosis and the promotion of mitochondrial activity. Consequently, this ultimately confers resistance to chemotherapy in LUAD. Furthermore, the administration of metformin, which blocks mitochondrial oxidative phosphorylation (OXPHOS), can restore sensitivity to drug resistance in LUAD. Taken together, these findings provide substantial evidence supporting the notion that FAM83B enhances chemotherapy resistance in LUAD through the upregulation of mitochondrial metabolism and the inhibition of apoptosis.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Epidermal growth factor receptor (EGFR) [2]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Missense mutation
p.T790M
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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-
S
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
M
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
L
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
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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
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A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
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V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 MGB SNP detection kit assay; Mutation Detection assay
Experiment for
Drug Resistance		 Digital PCR assay
Mechanism Description Resistance mechanisms to EGFR-TkI therapy in EGFR-mutated NSCLC include secondary EGFR T790M mutation, c-Met amplification, PIk3CA mutation, and transformation to small-cell lung cancer.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Aldo-keto reductase family 1 member B10 (AKR1B10) [5]
Metabolic Type Glucose metabolism
Sensitive Disease Lung cancer brain metastasis [ICD-11: 2C25.3]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Lung cancer [ICD-11: 2C25]
The Specified Disease Lung cancer brain metastasis
The Studied Tissue Lung tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.92E-01
Fold-change: 2.98E-01
Z-score: 1.31E+00
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model AKR1B10 knockdown PC9-BrM3 cells Lung Homo sapiens (Human) CVCL_XA19
Experiment for
Drug Resistance		 Cell viability assay; Clonogenicity assay; Cell apoptosis assay
Mechanism Description Metabolic profiling revealed that AKR1B10 prominently facilitated the Warburg metabolism characterized by the overproduction of lactate. Glycolysis regulated by AKR1B10 is vital for the resistance to PEM. In mechanism, AKR1B10 promoted glycolysis by regulating the expression of lactate dehydrogenase (LDHA) and the increased lactate, acts as a precursor that stimulates histone lactylation (H4K12la), activated the transcription of CCNB1 and accelerated the DNA replication and cell cycle.
Pleural mesothelioma [ICD-11: 2C26]
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: Thymidylate synthase (TYMS) [3]
Resistant Disease Malignant pleural mesothelioma [ICD-11: 2C26.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model MSTO-211H cells Lung Homo sapiens (Human) CVCL_1430
Plat-A cells Hepato Homo sapiens (Human) CVCL_B489
TCC-MESO-2 cells Bone and hypodermis Homo sapiens (Human) CVCL_E264
Experiment for
Molecule Alteration		 Western blotting assay
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description TYMS overexpression significantly increased drug resistance in the parental cells.The results of chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) assays suggested that H3K27 acetylation in the 5'-UTR of TYMS may promote its expression in drug-resistant cells.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-379 [1]
Sensitive Disease Malignant pleural mesothelioma [ICD-11: 2C26.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell proliferation Inhibition hsa05200
In Vitro Model MSTO-211H cells Lung Homo sapiens (Human) CVCL_1430
ACC-MESO1 cells Lung Homo sapiens (Human) CVCL_5113
ACC-MESO4 cells Lung Homo sapiens (Human) CVCL_5114
NCI-H2052 cells Lung Homo sapiens (Human) CVCL_1518
NCI-H2452 cells Lung Homo sapiens (Human) CVCL_1553
NCI-H28 cells Lung Homo sapiens (Human) CVCL_1555
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description miR-379 and miR-411 play a key role in the carcinogenesis of MPM cells by targeting IL-18 and contributing to the sensitivity of MPM cells to SAHA and PEM.
Key Molecule: hsa-mir-411 [1]
Sensitive Disease Malignant pleural mesothelioma [ICD-11: 2C26.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell proliferation Inhibition hsa05200
In Vitro Model MSTO-211H cells Lung Homo sapiens (Human) CVCL_1430
ACC-MESO1 cells Lung Homo sapiens (Human) CVCL_5113
ACC-MESO4 cells Lung Homo sapiens (Human) CVCL_5114
NCI-H2052 cells Lung Homo sapiens (Human) CVCL_1518
NCI-H2452 cells Lung Homo sapiens (Human) CVCL_1553
NCI-H28 cells Lung Homo sapiens (Human) CVCL_1555
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description miR-379 and miR-411 play a key role in the carcinogenesis of MPM cells by targeting IL-18 and contributing to the sensitivity of MPM cells to SAHA and PEM.
Key Molecule: hsa-mir-16 [7]
Sensitive Disease Malignant pleural mesothelioma [ICD-11: 2C26.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model MET-5A cells Lung Homo sapiens (Human) CVCL_3749
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 MTT assay; Colony formation assay
Mechanism Description Growth inhibition caused by miR-16 correlated with downregulation of target genes including Bcl-2 and CCND1, and miR-16 re-expression sensitised MPM cells to pemetrexed and gemcitabine.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Interleukin-18 (IL18) [1]
Sensitive Disease Malignant pleural mesothelioma [ICD-11: 2C26.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell proliferation Inhibition hsa05200
In Vitro Model MSTO-211H cells Lung Homo sapiens (Human) CVCL_1430
ACC-MESO1 cells Lung Homo sapiens (Human) CVCL_5113
ACC-MESO4 cells Lung Homo sapiens (Human) CVCL_5114
NCI-H2052 cells Lung Homo sapiens (Human) CVCL_1518
NCI-H2452 cells Lung Homo sapiens (Human) CVCL_1553
NCI-H28 cells Lung Homo sapiens (Human) CVCL_1555
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description miR-379 and miR-411 play a key role in the carcinogenesis of MPM cells by targeting IL-18 and contributing to the sensitivity of MPM cells to SAHA and PEM.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [7]
Sensitive Disease Malignant pleural mesothelioma [ICD-11: 2C26.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model MET-5A cells Lung Homo sapiens (Human) CVCL_3749
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Colony formation assay
Mechanism Description Growth inhibition caused by miR-16 correlated with downregulation of target genes including Bcl-2 and CCND1, and miR-16 re-expression sensitised MPM cells to pemetrexed and gemcitabine.
Key Molecule: G1/S-specific cyclin-D1 (CCND1) [7]
Sensitive Disease Malignant pleural mesothelioma [ICD-11: 2C26.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model MET-5A cells Lung Homo sapiens (Human) CVCL_3749
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Colony formation assay
Mechanism Description Growth inhibition caused by miR-16 correlated with downregulation of target genes including Bcl-2 and CCND1, and miR-16 re-expression sensitised MPM cells to pemetrexed and gemcitabine.
References
Ref 1 MiR-379/411 cluster regulates IL-18 and contributes to drug resistance in malignant pleural mesothelioma. Oncol Rep. 2014 Dec;32(6):2365-72. doi: 10.3892/or.2014.3481. Epub 2014 Sep 16.
Ref 2 Noninvasive monitoring of the genetic evolution of EGFR-mutant non-small-cell lung cancer by analyzing circulating tumor DNA during combination chemotherapy with gefitinib and pemetrexed or S-1. Onco Targets Ther. 2016 Aug 24;9:5287-95. doi: 10.2147/OTT.S105976. eCollection 2016.
Ref 3 Upregulation of Thymidylate Synthase Induces Pemetrexed Resistance in Malignant Pleural Mesothelioma .Front Pharmacol. 2021 Sep 27;12:718675. doi: 10.3389/fphar.2021.718675. eCollection 2021. 10.3389/fphar.2021.718675
Ref 4 Antiaging gene Klotho regulates epithelial-mesenchymal transition and increases sensitivity to pemetrexed by inducing lipocalin-2 expression. Oncol Lett. 2021 May;21(5):418.
Ref 5 Warburg effect enhanced by AKR1B10 promotes acquired resistance to pemetrexed in lung cancer-derived brain metastasis. J Transl Med. 2023 Aug 16;21(1):547.
Ref 6 FAM83B regulates mitochondrial metabolism and anti-apoptotic activity in pulmonary adenocarcinoma. Apoptosis. 2024 Jun;29(5-6):743-756.
Ref 7 Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma. Ann Oncol. 2013 Dec;24(12):3128-35. doi: 10.1093/annonc/mdt412. Epub 2013 Oct 22.

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