Drug Information

Drug (ID: DG00115) and It's Reported Resistant Information

• Name: Lapatinib
• Synonyms: FMM; Tycerb; Lapatinib Ditosylate; Lapatinib [INN]; Lapatinib tosilate hydrate; GSK 572016; GSK572016; GW 572016; GW 572016X; GW572016; Lapatinib (INN); Tykerb (TN); Lapatinib, Tykerb, GW572016; N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]quinazolin-4-amine; N-{3-CHLORO-4-[(3-FLUOROBENZYL)OXY]PHENYL}-6-[5-({[2-(METHYLSULFONYL)ETHYL]AMINO}METHYL)-2-FURYL]-4-QUINAZOLINAMINE; N-(3-Chloro-4-((3-fluorophenyl)methoxy)phenyl)-6-(5-((2-methylsulfonylethylamino)methyl)-2-furyl)quinazolin-4-amine; N-(3-Chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine; 4-[[3-Chloro-4-(3-fluorobenzyloxy)phenyl]amino]-6-[5-[[(2-methanesulfonylethyl)amino]methyl]furan-2-yl]quinazoline; Lapatinib (ERBB2 inhibitor)
• Indication:
  In total 1 Indication(s)
  Breast cancer [ICD-11: 2C60]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Breast cancer [ICD-11: 2C60]; [2]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Breast cancer [ICD-11: 2C60]; [3]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [4]
• Target: Epidermal growth factor receptor (EGFR); EGFR_HUMAN; [1]
• Target: Erbb2 tyrosine kinase receptor (HER2); ERBB2_HUMAN; [1]
• Target: Eukaryotic elongation factor 2 kinase (eEF-2K); EF2K_HUMAN; [1]
• Formula: C29H26ClFN4O4S
• IsoSMILES: CS(=O)(=O)CCNCC1=CC=C(O1)C2=CC3=C(C=C2)N=CN=C3NC4=CC(=C(C=C4)OCC5=CC(=CC=C5)F)Cl
• InChI: 1S/C29H26ClFN4O4S/c1-40(36,37)12-11-32-16-23-7-10-27(39-23)20-5-8-26-24(14-20)29(34-18-33-26)35-22-6-9-28(25(30)15-22)38-17-19-3-2-4-21(31)13-19/h2-10,13-15,18,32H,11-12,16-17H2,1H3,(H,33,34,35)
• InChIKey: BCFGMOOMADDAQU-UHFFFAOYSA-N
• PubChem CID: 208908
• ChEBI ID: CHEBI:49603
• TTD Drug ID: D08CDI
• VARIDT ID: DR00120
• DrugBank ID: DB01259

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) [4]

• Molecule Alteration: Duplication; p.Y772_A775 (c.2314_2325)/p.A775_G776insYVMA
• 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

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [4]

• Molecule Alteration: Complex-indel; p.G776_776delinsVC (c.2326_2328delinsGTATGT)
• 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

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [4]

• 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

Gastric cancer [ICD-11: 2B72]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-494 [1]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: YCC1 cells; Gastric; Homo sapiens (Human); CVCL_9646
• In Vitro Model: YCC1-F cells; Gastric; Homo sapiens (Human); CVCL_9646
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR 494 inhibited the CIC phenotype and reversed resistance to lapatinib by inhibiting FGFR2 in HER2 positive gastric cancer.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [1]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: YCC1 cells; Gastric; Homo sapiens (Human); CVCL_9646
• In Vitro Model: YCC1-F cells; Gastric; Homo sapiens (Human); CVCL_9646
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR 494 inhibited the CIC phenotype and reversed resistance to lapatinib by inhibiting FGFR2 in HER2 positive gastric cancer.

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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

• Molecule Alteration: Missense mutation; p.V292E
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

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

• Molecule Alteration: Missense mutation; p.R705G
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

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

• Molecule Alteration: Missense mutation; p.L760F
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

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

• Molecule Alteration: Missense mutation; p.K284E
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

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

• Molecule Alteration: Missense mutation; p.I706T
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

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

• Molecule Alteration: Missense mutation; p.G696E
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

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

• Molecule Alteration: Missense mutation; p.A822V
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

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

• Molecule Alteration: Missense mutation; p.V292M
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

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

• Molecule Alteration: Missense mutation; p.P741S
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

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

• Molecule Alteration: Missense mutation; p.G288D
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

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

• Molecule Alteration: Missense mutation; p.E711K
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [6]

• Molecule Alteration: Missense mutation; p.L755S (c.2263_2264delCTinsAG)
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: HER2 signaling pathway; Activation; hsa04012
• In Vitro Model: AU565 cells; Breast; Homo sapiens (Human); CVCL_1074
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: BT474/AZ cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vivo Model: Athymic mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: HER2 reactivation through acquisition of the HER2L755S mutation was identified as a mechanism of acquired resistance to L-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [7]

• Molecule Alteration: Missense mutation; p.T798M (c.2393_2394delCAinsTG)
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vivo Model: Athymic female mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: HER2T798M sequencing assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.T798M (c.2393_2394delCAinsTG) in gene ERBB2 cause the resistance of Lapatinib by aberration of the drug's therapeutic target

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Breast cancer anti-estrogen resistance 4 (BCAR4) [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: ERRB2/3 signaling pathway; Activation; hsa04210
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: WST-1 proliferation assay
• Mechanism Description: Breast Cancer Anti-Estrogen Resistance 4 (BCAR4) Drives Proliferation of IPH-926 lobular Carcinoma Cells. Relative high BCAR4 mRNA expression was identified in IPH-926, a cell line derived from an endocrine-resistant lobular breast cancer. Moderate BCAR4 expression was evident in MDA-MB-134 and MDA-MB-453 breast cancer cells. BCAR4 protein was detected in breast cancer cells with ectopic (ZR-75-1-BCAR4) and endogenous (IPH-926, MDA-MB-453) BCAR4 mRNA expression. knockdown of BCAR4 inhibited cell proliferation. A similar effect was observed upon knockdown of ERBB2/3 and exposure to lapatinib, implying that BCAR4 acts in an ERBB2/3-dependent manner.BCAR4 encodes a functional protein, which drives proliferation of endocrine-resistant breast cancer cells. Lapatinib, a clinically approved EGFR/ERBB2 inhibitor, counteracts BCAR4-driven tumor cell growth, a clinical relevant observation.

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

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: ERRB2/3 signaling pathway; Activation; hsa04210
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST-1 proliferation assay
• Mechanism Description: Breast Cancer Anti-Estrogen Resistance 4 (BCAR4) Drives Proliferation of IPH-926 lobular Carcinoma Cells. Relative high BCAR4 mRNA expression was identified in IPH-926, a cell line derived from an endocrine-resistant lobular breast cancer. Moderate BCAR4 expression was evident in MDA-MB-134 and MDA-MB-453 breast cancer cells. BCAR4 protein was detected in breast cancer cells with ectopic (ZR-75-1-BCAR4) and endogenous (IPH-926, MDA-MB-453) BCAR4 mRNA expression. knockdown of BCAR4 inhibited cell proliferation. A similar effect was observed upon knockdown of ERBB2/3 and exposure to lapatinib, implying that BCAR4 acts in an ERBB2/3-dependent manner.BCAR4 encodes a functional protein, which drives proliferation of endocrine-resistant breast cancer cells. Lapatinib, a clinically approved EGFR/ERBB2 inhibitor, counteracts BCAR4-driven tumor cell growth, a clinical relevant observation.

Key Molecule: Receptor tyrosine-protein kinase erbB-3 (ERBB3) [3]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: ERRB2/3 signaling pathway; Activation; hsa04210
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST-1 proliferation assay
• Mechanism Description: Breast Cancer Anti-Estrogen Resistance 4 (BCAR4) Drives Proliferation of IPH-926 lobular Carcinoma Cells. Relative high BCAR4 mRNA expression was identified in IPH-926, a cell line derived from an endocrine-resistant lobular breast cancer. Moderate BCAR4 expression was evident in MDA-MB-134 and MDA-MB-453 breast cancer cells. BCAR4 protein was detected in breast cancer cells with ectopic (ZR-75-1-BCAR4) and endogenous (IPH-926, MDA-MB-453) BCAR4 mRNA expression. knockdown of BCAR4 inhibited cell proliferation. A similar effect was observed upon knockdown of ERBB2/3 and exposure to lapatinib, implying that BCAR4 acts in an ERBB2/3-dependent manner.BCAR4 encodes a functional protein, which drives proliferation of endocrine-resistant breast cancer cells. Lapatinib, a clinically approved EGFR/ERBB2 inhibitor, counteracts BCAR4-driven tumor cell growth, a clinical relevant observation.

Key Molecule: Tumor protein 63 (TP63) [2]

• Molecule Alteration: Splicing mutation; Splicing
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Growth arrest-specific protein 6 (GAS6) [2]

• Molecule Alteration: Splicing mutation; Splicing
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Cadherin-1 (CDH1) [5]

• Molecule Alteration: Missense mutation; p.V345A
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [5]

• Molecule Alteration: Missense mutation; p.V1676A
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Notch signaling pathway; Regulation; hsa04330
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [5]

• Molecule Alteration: Missense mutation; p.S1689P
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Notch signaling pathway; Regulation; hsa04330
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: GTPase Nras (NRAS) [5]

• Molecule Alteration: Missense mutation; p.V14A
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: GTPase Nras (NRAS) [5]

• Molecule Alteration: Missense mutation; p.F78L
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: GTPase Nras (NRAS) [5]

• Molecule Alteration: Missense mutation; p.F28S
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: GTPase Nras (NRAS) [5]

• Molecule Alteration: Missense mutation; p.A66T
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: DNA mismatch repair protein Mlh1 (MLH1) [5]

• Molecule Alteration: Missense mutation; p.V345A
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: DNA mismatch repair protein Mlh1 (MLH1) [5]

• Molecule Alteration: Missense mutation; p.R90Q
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: DNA mismatch repair protein Mlh1 (MLH1) [5]

• Molecule Alteration: Missense mutation; p.R74Q
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: DNA mismatch repair protein Mlh1 (MLH1) [5]

• Molecule Alteration: Missense mutation; p.A348V
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: GTPase Hras (HRAS) [5]

• Molecule Alteration: Missense mutation; p.V9A
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: GTPase Hras (HRAS) [5]

• Molecule Alteration: Missense mutation; p.T2A
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: GTPase Hras (HRAS) [5]

• Molecule Alteration: Missense mutation; p.S17N
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: GTPase Hras (HRAS) [5]

• Molecule Alteration: Missense mutation; p.Q61X
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: GTPase Hras (HRAS) [5]

• Molecule Alteration: Missense mutation; p.N26S
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: GTPase Hras (HRAS) [5]

• Molecule Alteration: Missense mutation; p.G12S
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: GTPase Hras (HRAS) [5]

• Molecule Alteration: Missense mutation; p.D54N
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: Adenylate cyclase-stimulating G alpha protein (GNAS) [5]

• Molecule Alteration: Missense mutation; p.R216L
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: Adenylate cyclase-stimulating G alpha protein (GNAS) [5]

• Molecule Alteration: Missense mutation; p.R216C
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: Adenylate cyclase-stimulating G alpha protein (GNAS) [5]

• Molecule Alteration: Missense mutation; p.R186H
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: Adenylate cyclase-stimulating G alpha protein (GNAS) [5]

• Molecule Alteration: Missense mutation; p.N203S
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: Adenylate cyclase-stimulating G alpha protein (GNAS) [5]

• Molecule Alteration: Missense mutation; p.M206V
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: Adenylate cyclase-stimulating G alpha protein (GNAS) [5]

• Molecule Alteration: Missense mutation; p.D214N
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: Adenylate cyclase-stimulating G alpha protein (GNAS) [5]

• Molecule Alteration: Missense mutation; p.D181G
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: Cadherin-1 (CDH1) [5]

• Molecule Alteration: Missense mutation; p.A348V
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: Cadherin-1 (CDH1) [5]

• Molecule Alteration: Missense mutation; p.R90Q
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: Cadherin-1 (CDH1) [5]

• Molecule Alteration: Missense mutation; p.R74Q
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [5]

• Molecule Alteration: Missense mutation; p.V1599M
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Notch signaling pathway; Regulation; hsa04330
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Key Molecule: Phosphatase and tensin homolog (PTEN) [8]

• Molecule Alteration: Structural variation; Copy number loss
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HER2-amplified breast cancer cells; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Multi-region sequencing assay; Single-cell sequencing assay
• Mechanism Description: Similarly, PTEN loss or PIk3CA mutation was found to lower the clinical benefit of lapatinib in HER2-amplified metastatic breast cancer and to be responsible for lapatinib resistance in breast cancer cell lines. Tumor-promoting mutations seem to be involved in three major biological processes: cell survival, sensitive to mutations in EGFR, HER2, PIk3CA, BRAF, PTEN, MYC and others; cell fate, influenced by mutations in APC, NOTCH, AR, GATA2, kLF4 and genomic stability, altered by mutations in TP53, ATM, BRCA1, BRCA2 and others.

Key Molecule: PI3-kinase alpha (PIK3CA) [8]

• Molecule Alteration: Mutation; .
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HER2-amplified breast cancer cells; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Multi-region sequencing assay; Single-cell sequencing assay
• Mechanism Description: Similarly, PTEN loss or PIk3CA mutation was found to lower the clinical benefit of lapatinib in HER2-amplified metastatic breast cancer and to be responsible for lapatinib resistance in breast cancer cell lines. Tumor-promoting mutations seem to be involved in three major biological processes: cell survival, sensitive to mutations in EGFR, HER2, PIk3CA, BRAF, PTEN, MYC and others; cell fate, influenced by mutations in APC, NOTCH, AR, GATA2, kLF4 and genomic stability, altered by mutations in TP53, ATM, BRCA1, BRCA2 and others.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-630 [9]

• 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: Breast cancer anti-estrogen resistance 4 (BCAR4) [10]

• 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 proliferation; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: BCAR4 expression strongly sensitised ZR-75-1 and MCF7 breast cancer cells to the combination of lapatinib and antioestrogens. Lapatinib interfered with phosphorylation of ERBB2 and its downstream mediators AkT, FAk, SHC, STAT5, and STAT6.

Key Molecule: hsa-mir-205 [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 growth; 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: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: RT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: Fluorescence-activated cell sorting assay
• Mechanism Description: The activation of the PI3k/Akt survival pathway, so critically important in tumorigenesis, is for the most part driven through phosphorylation of the kinase-inactive member HER3. miR-205, negatively regulating HER3, is able to inhibit breast cancer cell proliferation and improves the response to specific targeted therapies. The reintroduction of miR-205 in SkBr3 cells inhibits their clonogenic potential and increases the responsiveness to tyrosine-kinase inhibitors Gefitinib and Lapatinib, abrogating the HER3-mediated resistance and restoring a potent proapoptotic activity.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [9]

• 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.

Key Molecule: Receptor tyrosine-protein kinase erbB-3 (ERBB3) [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 growth; 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: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Luciferase target assay
• Experiment for Drug Resistance: Fluorescence-activated cell sorting assay
• Mechanism Description: The activation of the PI3k/Akt survival pathway, so critically important in tumorigenesis, is for the most part driven through phosphorylation of the kinase-inactive member HER3. miR-205, negatively regulating HER3, is able to inhibit breast cancer cell proliferation and improves the response to specific targeted therapies. The reintroduction of miR-205 in SkBr3 cells inhibits their clonogenic potential and increases the responsiveness to tyrosine-kinase inhibitors Gefitinib and Lapatinib, abrogating the HER3-mediated resistance and restoring a potent proapoptotic activity.

References

• Ref 1: miR 494 inhibits cancer initiating cell phenotypes and reverses resistance to lapatinib by downregulating FGFR2 in HER2 positive gastric cancer. Int J Mol Med. 2018 Aug;42(2):998-1007. doi: 10.3892/ijmm.2018.3680. Epub 2018 May 16.
• Ref 2: Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013 May 2;497(7447):108-12. doi: 10.1038/nature12065. Epub 2013 Apr 7.
• Ref 3: Breast Cancer Anti-Estrogen Resistance 4 (BCAR4) Drives Proliferation of IPH-926 lobular Carcinoma Cells. PLoS One. 2015 Aug 28;10(8):e0136845. doi: 10.1371/journal.pone.0136845. eCollection 2015.
• Ref 4: 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 5: Circulating-free DNA Mutation Associated with Response of Targeted Therapy in Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer. Chin Med J (Engl). 2017 Mar 5;130(5):522-529. doi: 10.4103/0366-6999.200542.
• Ref 6: HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2(+) Breast CancerClin Cancer Res. 2017 Sep 1;23(17):5123-5134. doi: 10.1158/1078-0432.CCR-16-2191. Epub 2017 May 9.
• Ref 7: Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2Clin Cancer Res. 2013 Oct 1;19(19):5390-401. doi: 10.1158/1078-0432.CCR-13-1038. Epub 2013 Aug 15.
• Ref 8: Mechanism-based cancer therapy: resistance to therapy, therapy for resistance. Oncogene. 2015 Jul;34(28):3617-26. doi: 10.1038/onc.2014.314. Epub 2014 Sep 29.
• Ref 9: 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 10: BCAR4 induces antioestrogen resistance but sensitises breast cancer to lapatinib. Br J Cancer. 2012 Sep 4;107(6):947-55. doi: 10.1038/bjc.2012.351. Epub 2012 Aug 14.
• Ref 11: microRNA-205 regulates HER3 in human breast cancer. Cancer Res. 2009 Mar 15;69(6):2195-200. doi: 10.1158/0008-5472.CAN-08-2920. Epub 2009 Mar 10.