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
• 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]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Lung cancer [ICD-11: 2C25]; [2]
• Target: Poly [ADP-ribose] polymerase (PARP); NOUNIPROTAC; [1]
• 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

  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

Prostate cancer [ICD-11: 2C82]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Prostate cancer associated transcript 1 (PCAT1) [3]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate adenocarcinoma
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.05E-25; Fold-change: 3.43E+00; Z-score: 1.10E+01
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: 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.

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Mitochondrial pyruvate carrier subunit 1 (MPC1) [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Six-to 8-week-old female immunocompromised NSG mice, with KP5 cells; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Of about 3000 genes in the screen, our data revealed that mitochondrial pyruvate carrier 1 (MPC1) is an essential factor in desensitizing nonsmall cell lung cancer (NSCLC) lung cancer lines to PARP inhibition. In contrast to NSCLC lung cancer cells, triple-negative breast cancer cells do not exhibit such desensitization following MPC1 loss and reprogram the tricarboxylic acid cycle and oxidative phosphorylation pathways to overcome PARPi treatment.

Breast cancer [ICD-11: 2C60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-182 [4]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: 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)

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [4]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: 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]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-506 [1]

• Sensitive Disease: Ovarian serous carcinoma [ICD-11: 2C73.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: CDK4/6-FOXM1 signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Homologous recombination-mediated repair pathway; Inhibition; hsa03440
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: 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)

Key Molecule: DNA repair protein RAD51 homolog 1 (RAD51) [1]

• Sensitive Disease: Ovarian serous carcinoma [ICD-11: 2C73.2]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: CDK4/6-FOXM1 signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Homologous recombination-mediated repair pathway; Inhibition; hsa03440
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: 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.

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: Metabolism-focused CRISPR screen unveils mitochondrial pyruvate carrier 1 as a critical driver for PARP inhibitor resistance in lung cancer. Mol Carcinog. 2024 Jun;63(6):1024-1037.
• 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.
• Ref 4: 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.