Drug Information

Drug (ID: DG00214) and It's Reported Resistant Information

• Name: Saracatinib
• Synonyms: H8H; AZD-0530; Saracatinib, AZD-0530, AZD0530; N-(5-Chloro-1,3-benzodioxol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine
• Indication:
  In total 3 Indication(s)
  Malignant haematopoietic neoplasm [ICD-11: 2B33]; Phase 2; [1]
  Osteosarcoma [ICD-11: 2B51]; Phase 2; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Phase 2; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (3 diseases)
  Breast invasive carcinoma [ICD-11: 2C61]; [2]
  Colon cancer [ICD-11: 2B90]; [2]
  Pancreatic cancer [ICD-11: 2C10]; [2]
• Target: Proto-oncogene c-Src (SRC); SRC_HUMAN; [1]
• Target: Tyrosine-protein kinase ABL1 (ABL); ABL1_HUMAN; [1]
• Formula: C27H32ClN5O5
• IsoSMILES: CN1CCN(CC1)CCOC2=CC3=C(C(=C2)OC4CCOCC4)C(=NC=N3)NC5=C(C=CC6=C5OCO6)Cl
• InChI: 1S/C27H32ClN5O5/c1-32-6-8-33(9-7-32)10-13-35-19-14-21-24(23(15-19)38-18-4-11-34-12-5-18)27(30-16-29-21)31-25-20(28)2-3-22-26(25)37-17-36-22/h2-3,14-16,18H,4-13,17H2,1H3,(H,29,30,31)
• InChIKey: OUKYUETWWIPKQR-UHFFFAOYSA-N
• PubChem CID: 10302451
• TTD Drug ID: D0M0XB
• DrugBank ID: DB11805

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

Lung cancer [ICD-11: 2C25]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase ULK1 (ULK1) [3]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.52E-01; Fold-change: -2.18E-02; Z-score: -4.52E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR106a/ULk1 signaling pathway; Inhibition; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Resazurin conversion assay
• Mechanism Description: Src inhibition results in autophagy activation in NSCLC cell lines. Combining Src with autophagy inhibition results in significant cell death. Induction of ULk1 upon Scr inhibition allows for autophagy activation. Src inhibition causes induction of the ULk1 targeting microRNA-106a. Expression of the "oncogenic" miR-106a sensitizes NSCLC cells to Src inhibition.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-106a [3]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR106a/ULk1 signaling pathway; Inhibition; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Resazurin conversion assay
• Mechanism Description: Src inhibition results in autophagy activation in NSCLC cell lines. Combining Src with autophagy inhibition results in significant cell death. Induction of ULk1 upon Scr inhibition allows for autophagy activation. Src inhibition causes induction of the ULk1 targeting microRNA-106a. Expression of the "oncogenic" miR-106a sensitizes NSCLC cells to Src inhibition.

Breast cancer [ICD-11: 2C60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PI3-kinase alpha (PIK3CA) [1]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Breast cancer [ICD-11: 2C60]
• The Specified Disease: Breast cancer
• The Studied Tissue: Breast tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.59E-38; Fold-change: -1.23E-01; Z-score: -1.46E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Transwell assay; Flow cytometry assay
• Mechanism Description: miR-19b-3p increases saracatinib sensitivity by inhibiting the PI3k/Akt pathway and miR-19b-3p directly bound to the 3'-UTR of PIk3CA and inhibited PIk3CA expression.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-19b-3p [1]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Transwell assay; Flow cytometry assay
• Mechanism Description: miR-19b-3p increases saracatinib sensitivity by inhibiting the PI3k/Akt pathway and miR-19b-3p directly bound to the 3'-UTR of PIk3CA and inhibited PIk3CA expression.

Colon cancer [ICD-11: 2B90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Pyruvate dehydrogenase (PDH) [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Human colon cancer [ICD-11: 2B90.0]
• Molecule Alteration: Phosphorylation; tyrosine-289
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Mechanism Description: The results suggest that Src contributes to the Warburg phenotype by inactivating PDH through tyrosine phosphorylation, and the metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. Combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy.

Pancreatic cancer [ICD-11: 2C10]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Pyruvate dehydrogenase (PDH) [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Molecule Alteration: Phosphorylation; tyrosine-289
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: AsPC1 pancreatic cancer cells; Pancreas; Homo sapiens (Human); CVCL_0152
• Mechanism Description: The results suggest that Src contributes to the Warburg phenotype by inactivating PDH through tyrosine phosphorylation, and the metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. Combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy.

Breast invasive carcinoma [ICD-11: 2C61]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Pyruvate dehydrogenase (PDH) [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Mammary carcinoma [ICD-11: 2C61.1]
• Molecule Alteration: Phosphorylation; tyrosine-289
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 4T1 mammary carcinoma cells; Breast; Mus musculus (Mouse); CVCL_0125
• Mechanism Description: The results suggest that Src contributes to the Warburg phenotype by inactivating PDH through tyrosine phosphorylation, and the metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. Combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy.

References

• Ref 1: miR-19b-3p inhibits breast cancer cell proliferation and reverses saracatinib-resistance by regulating PI3K/Akt pathway. Arch Biochem Biophys. 2018 May 1;645:54-60. doi: 10.1016/j.abb.2018.03.015. Epub 2018 Mar 14.
• Ref 2: Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine-289 phosphorylation. Oncotarget. 2016 May 3;7(18):25113-24.
• Ref 3: MicroRNA-106a targets autophagy and enhances sensitivity of lung cancer cells to Src inhibitors. Lung Cancer. 2017 May;107:73-83. doi: 10.1016/j.lungcan.2016.06.004. Epub 2016 Jun 14.