Drug Information

Drug (ID: DG00244) and It's Reported Resistant Information

• Name: Neratinib
• Synonyms: Neratinib (ERBB2 inhibitor)
• Indication:
  In total 1 Indication(s)
  Breast cancer [ICD-11: 2C60]; Phase 3; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [2]
• Target: Epidermal growth factor receptor (EGFR); EGFR_HUMAN; [1]
• Target: ERBB2 messenger RNA (HER2 mRNA); ERBB2_HUMAN; [1]
• Target: Erbb2 tyrosine kinase receptor (HER2); ERBB2_HUMAN; [1]
• Target: Vascular endothelial growth factor receptor 2 (KDR); VGFR2_HUMAN; [1]
• Formula: C30H29ClN6O3
• IsoSMILES: CCOC1=C(C=C2C(=C1)N=CC(=C2NC3=CC(=C(C=C3)OCC4=CC=CC=N4)Cl)C#N)NC(=O)/C=C/CN(C)C
• InChI: 1S/C30H29ClN6O3/c1-4-39-28-16-25-23(15-26(28)36-29(38)9-7-13-37(2)3)30(20(17-32)18-34-25)35-21-10-11-27(24(31)14-21)40-19-22-8-5-6-12-33-22/h5-12,14-16,18H,4,13,19H2,1-3H3,(H,34,35)(H,36,38)/b9-7+
• InChIKey: JWNPDZNEKVCWMY-VQHVLOKHSA-N
• PubChem CID: 9915743
• ChEBI ID: CHEBI:61397
• TTD Drug ID: D0Q9CY
• INTEDE ID: DR1887
• DrugBank ID: DB11828

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  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

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [2]

• Molecule Alteration: Duplication; p.G778_P780 (c.2332_2340)/p.780_Y781insGSP
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Sanger cDNA sequencing assay
• Experiment for Drug Resistance: CCK-8 assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [2]

• Molecule Alteration: Duplication; p.Y772_A775 (c.2314_2325)/p.A775_G776insYVMA
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Sanger cDNA sequencing assay
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [2]

• Molecule Alteration: Complex-indel; p.G776_776delinsVC (c.2326_2328delinsGTATGT)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Sanger cDNA sequencing assay
• Experiment for Drug Resistance: CCK-8 assay

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-630 [1]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: HCC1954 cells; Breast; Homo sapiens (Human); CVCL_1259
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism that at least partly, involve miR-630's regulation of IGF1R. Blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby introducing miR-630 into cells reduced cellular aggression while inhibition of miR-630 induced a more aggressive cellular phenotype.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [3]

• Molecule Alteration: Missense mutation; p.L755S (c.2263_2264delCTinsAG)
• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [3]

• Molecule Alteration: Complex-indel; p.L755_E757delinsS (c.2263_2271delinsAGC)
• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [3]

• Molecule Alteration: Duplication; p.Y772_A775 (c.2314_2325)
• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [3]

• Molecule Alteration: Missense mutation; p.V777L (c.2329G>C)
• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [3]

• Molecule Alteration: Duplication; p.G778_P780 (c.2332_2340)
• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [3]

• Molecule Alteration: Missense mutation; p.L869R (c.2606T>G)
• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [3]

• Molecule Alteration: Missense mutation; p.S310F (c.929C>T)
• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [1]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: HCC1954 cells; Breast; Homo sapiens (Human); CVCL_1259
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism that at least partly, involve miR-630's regulation of IGF1R. Blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby introducing miR-630 into cells reduced cellular aggression while inhibition of miR-630 induced a more aggressive cellular phenotype.

References

• Ref 1: miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer. Mol Cancer. 2014 Mar 24;13:71. doi: 10.1186/1476-4598-13-71.
• Ref 2: Activity of a novel HER2 inhibitor, poziotinib, for HER2 exon 20 mutations in lung cancer and mechanism of acquired resistance: An in vitro studyLung Cancer. 2018 Dec;126:72-79. doi: 10.1016/j.lungcan.2018.10.019. Epub 2018 Oct 17.
• Ref 3: HER kinase inhibition in patients with HER2- and HER3-mutant cancersNature. 2018 Feb 8;554(7691):189-194. doi: 10.1038/nature25475. Epub 2018 Jan 31.