Drug Information

Drug (ID: DG00074) and It's Reported Resistant Information

• Name: Afatinib
• Synonyms: Afatinib; Tomtovok; Tovok; BIBW-2992; Tovok (TN); Tovok, BIBW2992; (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[(3S)-tetrahydrofuran-3-yloxy]quinazolin-6-yl}-4-(dimethylamino)but-2-enamide; EGFR inhibitor 2nd gens
• Indication:
  In total 1 Indication(s)
  Lung cancer [ICD-11: 2C25]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Chordoma [ICD-11: 2B5J]; [2]
  Lung cancer [ICD-11: 2C25]; [3], [4], [5]
  Oesophagogastric cancer [ICD-11: 2B71]; [6]
• Target: Epidermal growth factor receptor (EGFR); EGFR_HUMAN; [1]
• Target: Erbb2 tyrosine kinase receptor (HER2); ERBB2_HUMAN; [1]
• Formula: C24H25ClFN5O3
• IsoSMILES: CN(C)C/C=C/C(=O)NC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC(=C(C=C3)F)Cl)O[C@H]4CCOC4
• InChI: 1S/C24H25ClFN5O3/c1-31(2)8-3-4-23(32)30-21-11-17-20(12-22(21)34-16-7-9-33-13-16)27-14-28-24(17)29-15-5-6-19(26)18(25)10-15/h3-6,10-12,14,16H,7-9,13H2,1-2H3,(H,30,32)(H,27,28,29)/b4-3+/t16-/m0/s1
• InChIKey: ULXXDDBFHOBEHA-CWDCEQMOSA-N
• PubChem CID: 10184653
• ChEBI ID: CHEBI:61390
• TTD Drug ID: D05UFG
• VARIDT ID: DR00354
• DrugBank ID: DB08916

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

Chordoma [ICD-11: 2B5J]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Y-box-binding protein 1 (YBX1) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Chordoma [ICD-11: 2B5J.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR/AKT signaling pathway; Regulation; hsa04012
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: Chordoma tissue; N.A.
• In Vivo Model: NOD/SCID/IL2Rgamma null (NOG) mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: YBX1 regulated protein expression of pEGFR, pAKT and its downstream target genes that influenced cell apoptosis, cell cycle transition and cell invasion. YBX1 activated the EGFR/AKT pathway in chordoma and YBX1-induced elevated expression of key molecules in the EGFR/AKT pathway were downregulated by EGFR and AKT pathway inhibitors. These in vitro results were further confirmed by in vivo data. These data showed that YBX1 promoted tumorigenesis and progression in spinal chordoma via the EGFR/AKT pathway. YBX1 might serve as a prognostic and predictive biomarker, as well as a rational therapeutic target, for chordoma.

Oesophagogastric cancer [ICD-11: 2B71]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Hepatocyte growth factor receptor (MET) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophagogastric cancer [ICD-11: 2B71.1]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We find that concurrent amplification of EGFR and ERBB2 is associated with response to the HER kinase inhibitor afatinib in patients with trastuzumab-refractory EG cancer. Heterogeneous uptake of 89Zr-trastuzumab measured noninvasively by PET was associated with disease progression. Analyses of multiple disease sites sampled at the time of disease progression indicated several potential mediators of afatinib resistance, including loss of EGFR amplification and gain of MET amplification.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Epidermal growth factor receptor (EGFR) [6]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophagogastric cancer [ICD-11: 2B71.1]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: In summary, we find that concurrent amplification of EGFR and ERBB2 is associated with response to the HER kinase inhibitor afatinib in patients with trastuzumab-refractory EG cancer. Heterogeneous uptake of 89Zr-trastuzumab measured noninvasively by PET was associated with disease progression. Analyses of multiple disease sites sampled at the time of disease progression indicated several potential mediators of afatinib resistance, including loss of EGFR amplification and gain of MET amplification.

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Epidermal growth factor receptor (EGFR) [3], [4], [5]

• Molecule Alteration: Missense mutation; p.T790M
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Exon sequencing assay
• Experiment for Drug Resistance: Progression-free and post-progression survival asaay
• Mechanism Description: T790M was detected in half of the lung adenocarcinoma after acquiring resistance to afatinib. T790M is still the major acquired resistance mechanism. First-generation EGFR TkI exposure did not influence the prevalence of T790M in lung cancer acquired resistance to afatinib.

Key Molecule: Epidermal growth factor receptor (EGFR) [7], [8], [9]

• 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: Directional sequencing assay; Direct sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Progression-free and post-progression survival asaay; Analysis of progression-free survival (PFS) assay; Overall survival assay
• Mechanism Description: The identification of T790M as acquired resistance mechanism was clinically feasible. Although T790M had no prognostic or predictive role in the present study, further research is necessary to identify patients with T790M-mutant tumors who might benefit from newly developed T790M-specific TkIs.T790M is likely a common resistance mechanism in patients treated with first-line afatinib. Although repeat biopsies at progression are crucial in elucidating resistance mechanisms, this study suggests that clinical and technical issues often limit their feasibility, highlighting the importance of developing.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Hepatocyte growth factor receptor (MET) [10]

• Molecule Alteration: Missense mutation; p.D1228V
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Our in vitro findings demonstrate that MET D1228V induces resistance to type I MET TkIs through impaired drug binding while sensitivity to type II MET TkIs is maintained.

Key Molecule: Merlin (NF2) [5]

• Molecule Alteration: Missense mutation; p.R198*
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• Experiment for Molecule Alteration: Deep amplicon-based resequencing assay; Whole exome sequencing assay
• Experiment for Drug Resistance: Magnetic resonance imaging assay; Computerized tomography assay
• Mechanism Description: Whole exome sequencing (WES) of the A+C-resistant #16 and #24 tumors did not detect mutations in 23 mTOR-pathway related genes, strongly suggesting that non-mutational processes account for sustained activation of this pathway in these tumors.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: BLACAT1 overlapping LEMD1 locus (BLACAT1) [1]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• 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: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vivo Model: BALB/c nude xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis; Immunohistochemistry
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: BLACAT1 was up-regulated in afatinib-resistant NSCLC cells and knockdown of BLACAT1 reversed the resistance of afatinib to NSCLC cells by modulating STAT3 signalling.

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 [11]

• 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.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [11]

• 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: Knockdown of lncRNA BLACAT1 reverses the resistance of afatinib to non-small cell lung cancer via modulating STAT3 signalling. J Drug Target. 2020 Mar;28(3):300-306. doi: 10.1080/1061186X.2019.1650368. Epub 2019 Aug 5.
• Ref 2: Y-box binding protein-1 promotes tumorigenesis and progression via the epidermal growth factor receptor/AKT pathway in spinal chordoma .Cancer Sci. 2019 Jan;110(1):166-179. doi: 10.1111/cas.13875. Epub 2018 Dec 19. 10.1111/cas.13875
• Ref 3: Phase I study of continuous afatinib (BIBW 2992) in patients with advanced non-small cell lung cancer after prior chemotherapy/erlotinib/gefitinib (LUX-Lung 4). Cancer Chemother Pharmacol. 2012 Apr;69(4):891-9. doi: 10.1007/s00280-011-1738-1. Epub 2011 Nov 10.
• Ref 4: The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor. Mol Cancer Ther. 2012 Mar;11(3):784-91. doi: 10.1158/1535-7163.MCT-11-0750. Epub 2012 Jan 6.
• Ref 5: Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1. Cell Rep. 2014 May 22;7(4):999-1008. doi: 10.1016/j.celrep.2014.04.014. Epub 2014 May 9.
• Ref 6: EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer .Cancer Discov. 2019 Feb;9(2):199-209. doi: 10.1158/2159-8290.CD-18-0598. Epub 2018 Nov 21. 10.1158/2159-8290.CD-18-0598
• Ref 7: Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):E2127-33. doi: 10.1073/pnas.1203530109. Epub 2012 Jul 6.
• Ref 8: Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells. Cancer Res. 2013 May 15;73(10):3051-61. doi: 10.1158/0008-5472.CAN-12-4136. Epub 2013 Mar 29.
• Ref 9: Clinical implications of T790M mutation in patients with acquired resistance to EGFR tyrosine kinase inhibitors. Lung Cancer. 2013 Nov;82(2):294-8. doi: 10.1016/j.lungcan.2013.08.023. Epub 2013 Sep 3.
• Ref 10: Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer. Cancer Discov. 2016 Dec;6(12):1334-1341. doi: 10.1158/2159-8290.CD-16-0686. Epub 2016 Sep 30.
• Ref 11: 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.