Drug Information

Drug (ID: DG00202) and It's Reported Resistant Information
Name
Olaparib
Synonyms
AZD 2281; AZD2281; AZD-2281; Acylpiperazine analogue, 47; KU-0059436; KU-59436; Olaparib, KU-0059436, AZD2281,KU0059436, AZD2281; 4-[(3-{[4-Cyclopropylcarbonyl)piperazin-4-yl]carbonyl}-4-fluorophenyl)methyl]phtalazin-1(2H)-one; 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one
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Indication
In total 3 Indication(s)
Ovarian cancer [ICD-11: 2C73]
Approved
[1]
Pancreatic cancer [ICD-11: 2C10]
Phase 3
[1]
Prostate cancer [ICD-11: 2C82]
Phase 3
[1]
Structure
Target Poly [ADP-ribose] polymerase (PARP) NOUNIPROTAC [1]
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Formula
C24H23FN4O3
IsoSMILES
C1CC1C(=O)N2CCN(CC2)C(=O)C3=C(C=CC(=C3)CC4=NNC(=O)C5=CC=CC=C54)F
InChI
1S/C24H23FN4O3/c25-20-8-5-15(14-21-17-3-1-2-4-18(17)22(30)27-26-21)13-19(20)24(32)29-11-9-28(10-12-29)23(31)16-6-7-16/h1-5,8,13,16H,6-7,9-12,14H2,(H,27,30)
InChIKey
FDLYAMZZIXQODN-UHFFFAOYSA-N
PubChem CID
23725625
ChEBI ID
CHEBI:83766
TTD Drug ID
D0J9HW
VARIDT ID
DR00221
INTEDE ID
DR1188
DrugBank ID
DB09074
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
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Breast cancer [ICD-11: 2C60]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-182 [2]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
In Vivo Model CD1 nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 Clonogenic assay
Mechanism Description miR-182-mediated down-regulation of BRCA1 impedes DNA repair, and lead to Olaparib resistance.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [2]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
In Vivo Model CD1 nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Clonogenic assay
Mechanism Description miR-182-mediated down-regulation of BRCA1 impedes DNA repair, and lead to Olaparib resistance.
Ovarian cancer [ICD-11: 2C73]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-506 [1]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Ovarian serous carcinoma [ICD-11: 2C73.2]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation CDK4/6-FOXM1 signaling pathway Regulation hsa04218
Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
Homologous recombination-mediated repair pathway Inhibition hsa03440
In Vitro Model SkOV3 cells Ovary Homo sapiens (Human) CVCL_0532
Hela cells Cervix uteri Homo sapiens (Human) CVCL_0030
Hey A8 cells Ovary Homo sapiens (Human) CVCL_8878
OVCA433 cells Ovary Homo sapiens (Human) CVCL_0475
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-506 overexpression sensitized ovarian cancer cells to cisplatin or to a commercially available PARP inhibitor (olaparib) due to miR-506 overexpression decreasing RAD51 levels and homologous recombination efficiency.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: DNA repair protein RAD51 homolog 1 (RAD51) [1]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Ovarian serous carcinoma [ICD-11: 2C73.2]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation CDK4/6-FOXM1 signaling pathway Regulation hsa04218
Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
Homologous recombination-mediated repair pathway Inhibition hsa03440
In Vitro Model SkOV3 cells Ovary Homo sapiens (Human) CVCL_0532
Hela cells Cervix uteri Homo sapiens (Human) CVCL_0030
Hey A8 cells Ovary Homo sapiens (Human) CVCL_8878
OVCA433 cells Ovary Homo sapiens (Human) CVCL_0475
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-506 overexpression sensitized ovarian cancer cells to cisplatin or to a commercially available PARP inhibitor (olaparib) due to miR-506 overexpression decreasing RAD51 levels and homologous recombination efficiency.
Prostate cancer [ICD-11: 2C82]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Prostate cancer associated transcript 1 (PCAT1) [3]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model DU-145 cells Prostate Homo sapiens (Human) CVCL_0105
LNCaP cells Prostate Homo sapiens (Human) CVCL_0395
PC3 cells Prostate Homo sapiens (Human) CVCL_0035
RWPE cells Prostate Homo sapiens (Human) CVCL_1736
In Vivo Model SCID nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 WST assay
Mechanism Description PCAT-1 expressing cells exhibit a BRCA-like phenotype, resulting in cell sensitization to PARP1 inhibitors. In human prostate cancer tissues, high PCAT-1 expression predicts for low BRCA2 expression, supporting our observations in model systems.
References
Ref 1 Augmentation of response to chemotherapy by microRNA-506 through regulation of RAD51 in serous ovarian cancers. J Natl Cancer Inst. 2015 May 20;107(7):djv108. doi: 10.1093/jnci/djv108. Print 2015 Jul.
Ref 2 miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol Cell. 2011 Jan 21;41(2):210-20. doi: 10.1016/j.molcel.2010.12.005. Epub 2010 Dec 30.
Ref 3 PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer. Cancer Res. 2014 Mar 15;74(6):1651-60. doi: 10.1158/0008-5472.CAN-13-3159. Epub 2014 Jan 28.

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