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
• Indication:
  In total 1 Indication(s)
  Pleural mesothelioma [ICD-11: 2C26]; Approved; [1]
• 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]
• Target: Candida Thymidylate synthase (Candi TMP1); TYSY_CANAL; [1]
• 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

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Epidermal growth factor receptor (EGFR) [2]

• Molecule Alteration: Missense mutation; p.T790M
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• 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.

Pleural mesothelioma [ICD-11: 2C26]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Thymidylate synthase (TYMS) [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MSTO-211H cells; Lung; Homo sapiens (Human); CVCL_1430
• In Vitro Model: Plat-A cells; Hepato; Homo sapiens (Human); CVCL_B489
• In Vitro Model: 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)

Key Molecule: hsa-mir-379 [1]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MSTO-211H cells; Lung; Homo sapiens (Human); CVCL_1430
• In Vitro Model: ACC-MESO1 cells; Lung; Homo sapiens (Human); CVCL_5113
• In Vitro Model: ACC-MESO4 cells; Lung; Homo sapiens (Human); CVCL_5114
• In Vitro Model: NCI-H2052 cells; Lung; Homo sapiens (Human); CVCL_1518
• In Vitro Model: NCI-H2452 cells; Lung; Homo sapiens (Human); CVCL_1553
• In Vitro Model: 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]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MSTO-211H cells; Lung; Homo sapiens (Human); CVCL_1430
• In Vitro Model: ACC-MESO1 cells; Lung; Homo sapiens (Human); CVCL_5113
• In Vitro Model: ACC-MESO4 cells; Lung; Homo sapiens (Human); CVCL_5114
• In Vitro Model: NCI-H2052 cells; Lung; Homo sapiens (Human); CVCL_1518
• In Vitro Model: NCI-H2452 cells; Lung; Homo sapiens (Human); CVCL_1553
• In Vitro Model: 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 [4]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• 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)

Key Molecule: Interleukin-18 (IL18) [1]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MSTO-211H cells; Lung; Homo sapiens (Human); CVCL_1430
• In Vitro Model: ACC-MESO1 cells; Lung; Homo sapiens (Human); CVCL_5113
• In Vitro Model: ACC-MESO4 cells; Lung; Homo sapiens (Human); CVCL_5114
• In Vitro Model: NCI-H2052 cells; Lung; Homo sapiens (Human); CVCL_1518
• In Vitro Model: NCI-H2452 cells; Lung; Homo sapiens (Human); CVCL_1553
• In Vitro Model: 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) [4]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• 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 blotting 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) [4]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• 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 blotting 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: 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.