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)
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Indication
In total 1 Indication(s)
Breast cancer [ICD-11: 2C60]
Approved
[1]
Structure
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 Validated by in-vivo Model for This Drug (1 diseases)
Breast cancer [ICD-11: 2C60]
[3]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
Breast cancer [ICD-11: 2C60]
[4]
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
[5]
Target Epidermal growth factor receptor (EGFR) EGFR_HUMAN [1]
Erbb2 tyrosine kinase receptor (HER2) ERBB2_HUMAN [1]
Eukaryotic elongation factor 2 kinase (eEF-2K) EF2K_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
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
  IDUE: Irregularity in Drug Uptake and Drug Efflux
  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
Click to Show/Hide the Resistance Disease of This Class
Gastric cancer [ICD-11: 2B72]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [1]
Sensitive Disease Gastric cancer [ICD-11: 2B72.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Gastric cancer [ICD-11: 2B72]
The Specified Disease Gastric cancer
The Studied Tissue Gastric tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 5.05E-02
Fold-change: -1.04E-01
Z-score: -4.09E+00
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
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.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-494 [1]
Sensitive Disease Gastric cancer [ICD-11: 2B72.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
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
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.
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [5]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Duplication
p.Y772_A775 (c.2314_2325)/p.A775_G776insYVMA
 Molecule Info 
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) [5]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Complex-indel
p.G776_776delinsVC (c.2326_2328delinsGTATGT)
 Molecule Info 
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) [5]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Duplication
p.G778_P780 (c.2332_2340)/p.780_Y781insGSP
 Molecule Info 
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]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Epidermal growth factor receptor (EGFR) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.V292E
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.R705G
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.L760F
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.K284E
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.I706T
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.G696E
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.A822V
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.V292M
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.P741S
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.G288D
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.E711K
 Molecule Info 
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) [7]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.L755S (c.2263_2264delCTinsAG)
 Molecule Info 
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
SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474/AZ cells Breast Homo sapiens (Human) CVCL_0179
In Vivo Model Athymic mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot 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) [8]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.T798M (c.2393_2394delCAinsTG)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model BT474 cells Breast Homo sapiens (Human) CVCL_0179
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
  Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: P-glycoprotein (ABCB1) [3]
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vivo Model Athymic nude mice model Mus musculus
Experiment for
Molecule Alteration		 CD spectroscopy assay; SDS-PAGE assay
Experiment for
Drug Resistance		 Cell viability assay; Fluorescence microscope assay
Mechanism Description HER2-positive breast cancer constitutes 20 % of reported cases, characterized by excessive expression of HER2 receptors, pivotal in cell signaling and growth. Immunotherapy, the established treatment, often leads to multidrug resistance and tumor recurrence. There's a critical need for an effective strategy delaying drug resistance onset and ensuring cancer cell eradication. This study aimed to develop nanoparticles using human serum albumin (HSA) coupled with vitamin E (alpha-tocopherol succinate), loaded with a tyrosine kinase inhibitor (TKI) or aromatase inhibitor (AI). Nanoparticles were formed via desolvation, where HSA(VE) conjugates self-organized into a nanoparticle structure, incorporating TKI/AI either through chemical conjugation or direct binding to HSA. Physico-chemical analyses-such as infrared spectroscopy (IR), gel permeation chromatography (GPC), UV, IR, and CD spectroscopy confirmed HSA(VE) binding and drug incorporation into nanoparticles, evaluating their drug entrapment, release efficiency. Cell viability assays and in-vitro experiments on resistant and sensitive cell lines demonstrated effective drug encapsulation and absorption over time. Both in vitro and in vivo studies demonstrated that a combination of Lapa@HSA(VE) NPs and Let@HSA(VE) NPs in the ratio 75:25 inhibited tumor development and enhanced apoptosis significantly compared to individual NP treatment and free drug. The combination NPs therapy exhibited significant efficacy even in Lapa-resistant cell lines.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Hras (HRAS) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.G12S
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.24  Å
PDB: 4OBE
Mutant Type Structure Method: X-ray diffraction Resolution: 1.71  Å
PDB: 7TLK
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.85
TM score: 0.93473
Amino acid change:
G12S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
S
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
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A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
Click to Show/Hide the Structure
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: Breast cancer anti-estrogen resistance 4 (BCAR4) [4]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Activation hsa05200
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) [4]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Activation hsa05200
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) [4]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Activation hsa05200
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]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Splicing mutation
Splicing
 Molecule Info 
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]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Splicing mutation
Splicing
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.V345A
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.V1676A
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Notch signaling pathway Regulation N.A.
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.S1689P
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Notch signaling pathway Regulation N.A.
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.V14A
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.F78L
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.F28S
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.A66T
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.V345A
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.R90Q
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.R74Q
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.A348V
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.V9A
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.T2A
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.S17N
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.Q61X
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.N26S
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.D54N
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.R216L
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.R216C
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.R186H
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.N203S
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.M206V
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.D214N
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.D181G
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.A348V
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.R90Q
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.R74Q
 Molecule Info 
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) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.V1599M
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Notch signaling pathway Regulation N.A.
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) [9]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Structural variation
Copy number loss
 Molecule Info 
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) [9]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Mutation
.
 Molecule Info 
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
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Transmembrane protease serine 2 (TMPRSS2) [10]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model SK-BR-3 cells Pleural effusion Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 MTT assay; Clonogenic assay
Mechanism Description Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from?Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and?Artemisia argyi?emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer.?
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-miR-630 [11]
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
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) [12]
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
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
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 [13]
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell growth Inhibition hsa05200
PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
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.
  Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Glycoprotein 60 (gp60) [3]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vivo Model Athymic nude mice model Mus musculus
Experiment for
Molecule Alteration		 CD spectroscopy assay; SDS-PAGE assay
Experiment for
Drug Resistance		 Cell viability assay; Fluorescence microscope assay
Mechanism Description HER2-positive breast cancer constitutes 20 % of reported cases, characterized by excessive expression of HER2 receptors, pivotal in cell signaling and growth. Immunotherapy, the established treatment, often leads to multidrug resistance and tumor recurrence. There's a critical need for an effective strategy delaying drug resistance onset and ensuring cancer cell eradication. This study aimed to develop nanoparticles using human serum albumin (HSA) coupled with vitamin E (alpha-tocopherol succinate), loaded with a tyrosine kinase inhibitor (TKI) or aromatase inhibitor (AI). Nanoparticles were formed via desolvation, where HSA(VE) conjugates self-organized into a nanoparticle structure, incorporating TKI/AI either through chemical conjugation or direct binding to HSA. Physico-chemical analyses-such as infrared spectroscopy (IR), gel permeation chromatography (GPC), UV, IR, and CD spectroscopy confirmed HSA(VE) binding and drug incorporation into nanoparticles, evaluating their drug entrapment, release efficiency. Cell viability assays and in-vitro experiments on resistant and sensitive cell lines demonstrated effective drug encapsulation and absorption over time. Both in vitro and in vivo studies demonstrated that a combination of Lapa@HSA(VE) NPs and Let@HSA(VE) NPs in the ratio 75:25 inhibited tumor development and enhanced apoptosis significantly compared to individual NP treatment and free drug. The combination NPs therapy exhibited significant efficacy even in Lapa-resistant cell lines.
Key Molecule: SPARC (SPARC) [3]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vivo Model Athymic nude mice model Mus musculus
Experiment for
Molecule Alteration		 CD spectroscopy assay; SDS-PAGE assay
Experiment for
Drug Resistance		 Cell viability assay; Fluorescence microscope assay
Mechanism Description HER2-positive breast cancer constitutes 20 % of reported cases, characterized by excessive expression of HER2 receptors, pivotal in cell signaling and growth. Immunotherapy, the established treatment, often leads to multidrug resistance and tumor recurrence. There's a critical need for an effective strategy delaying drug resistance onset and ensuring cancer cell eradication. This study aimed to develop nanoparticles using human serum albumin (HSA) coupled with vitamin E (alpha-tocopherol succinate), loaded with a tyrosine kinase inhibitor (TKI) or aromatase inhibitor (AI). Nanoparticles were formed via desolvation, where HSA(VE) conjugates self-organized into a nanoparticle structure, incorporating TKI/AI either through chemical conjugation or direct binding to HSA. Physico-chemical analyses-such as infrared spectroscopy (IR), gel permeation chromatography (GPC), UV, IR, and CD spectroscopy confirmed HSA(VE) binding and drug incorporation into nanoparticles, evaluating their drug entrapment, release efficiency. Cell viability assays and in-vitro experiments on resistant and sensitive cell lines demonstrated effective drug encapsulation and absorption over time. Both in vitro and in vivo studies demonstrated that a combination of Lapa@HSA(VE) NPs and Let@HSA(VE) NPs in the ratio 75:25 inhibited tumor development and enhanced apoptosis significantly compared to individual NP treatment and free drug. The combination NPs therapy exhibited significant efficacy even in Lapa-resistant cell lines.
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Dual specificity phosphatase 4 (DUSP4) [14]
Metabolic Type Redox metabolism
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model BT-474 cells Breast Homo sapiens (Human) CVCL_0179
Experiment for
Molecule Alteration		 RNA seq; Western blot analysis
Experiment for
Drug Resistance		 IC50 assay
Mechanism Description ur findings reveal that DUSP4 enhances therapeutic efficacy in HER2-positive BC by inhibiting the ROS pathway. Elevated DUSP4 levels correlate with increased sensitivity to HER2-targeted therapies and improved clinical outcomes. DUSP4 independently predicts disease-free survival (DFS) and overall survival (OS) in HER4-positive BC.
Key Molecule: Dual specificity phosphatase 4 (DUSP4) [14]
Metabolic Type Redox metabolism
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model SK-BR-3 cells Pleural effusion Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 RNA seq; Western blot analysis
Experiment for
Drug Resistance		 IC50 assay
Mechanism Description ur findings reveal that DUSP4 enhances therapeutic efficacy in HER2-positive BC by inhibiting the ROS pathway. Elevated DUSP4 levels correlate with increased sensitivity to HER2-targeted therapies and improved clinical outcomes. DUSP4 independently predicts disease-free survival (DFS) and overall survival (OS) in HER5-positive BC.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [11]
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
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) [13]
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell growth Inhibition hsa05200
PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
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.
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [3]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
Cell Pathway Regulation HER2 signaling pathway Inhibition hsa04012
In Vivo Model Athymic nude mice model Mus musculus
Experiment for
Molecule Alteration		 CD spectroscopy assay; SDS-PAGE assay
Experiment for
Drug Resistance		 Cell viability assay; Fluorescence microscope assay
Mechanism Description HER2-positive breast cancer constitutes 20 % of reported cases, characterized by excessive expression of HER2 receptors, pivotal in cell signaling and growth. Immunotherapy, the established treatment, often leads to multidrug resistance and tumor recurrence. There's a critical need for an effective strategy delaying drug resistance onset and ensuring cancer cell eradication. This study aimed to develop nanoparticles using human serum albumin (HSA) coupled with vitamin E (alpha-tocopherol succinate), loaded with a tyrosine kinase inhibitor (TKI) or aromatase inhibitor (AI). Nanoparticles were formed via desolvation, where HSA(VE) conjugates self-organized into a nanoparticle structure, incorporating TKI/AI either through chemical conjugation or direct binding to HSA. Physico-chemical analyses-such as infrared spectroscopy (IR), gel permeation chromatography (GPC), UV, IR, and CD spectroscopy confirmed HSA(VE) binding and drug incorporation into nanoparticles, evaluating their drug entrapment, release efficiency. Cell viability assays and in-vitro experiments on resistant and sensitive cell lines demonstrated effective drug encapsulation and absorption over time. Both in vitro and in vivo studies demonstrated that a combination of Lapa@HSA(VE) NPs and Let@HSA(VE) NPs in the ratio 75:25 inhibited tumor development and enhanced apoptosis significantly compared to individual NP treatment and free drug. The combination NPs therapy exhibited significant efficacy even in Lapa-resistant cell lines.
Unspecified carcinoma of unspecified site [ICD-11: 2D41]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Cystine/glutamate transporter (SLC7A11) [15]
Sensitive Disease krasg12c inhibitor resistant tumors [ICD-11: 2D41]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK 293T cells Kidney Homo sapiens (Human) CVCL_0063
MiaPaCa-2 cells Blood Homo sapiens (Human) CVCL_0428
NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
NCI-H23 cells Lung Homo sapiens (Human) CVCL_1547
Calu-1 cells Lung Homo sapiens (Human) CVCL_0608
In Vivo Model BALB/c athymic nude mice model Mus musculus
Experiment for
Molecule Alteration		 RT-qPCR; Western blot assay
Experiment for
Drug Resistance		 Cell viability assay; Immunohistochemical assay; Xenograft mouse assay
Mechanism Description The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells.
Head and neck cancer [ICD-11: 2D42]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Pan-HER family receptors (Pan-HERs) [16]
Sensitive Disease Head and neck cancer [ICD-11: 2D42.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
AKT/mTOR signaling pathway Inhibition hsa04150
In Vitro Model 4NQO-L cells Tongue Homo sapiens (Human) N.A.
4NQO-T cells Tongue Homo sapiens (Human) N.A.
In Vivo Model C57BL/6 J male mice model Mus musculus
Experiment for
Molecule Alteration		 Western blot assay; Immunohistochemistry; Immunofluorescence staining assay
Experiment for
Drug Resistance		 IC50 assay; Cell proliferation assay; CD8+ depletion assay
Mechanism Description Results: Activation and upregulation of EGFR and HER2/3 (pan-HERs) are the intrinsic mechanism of resistance to KRASG12Ci in 4NQO-L cells, and blocking pan-HERs signaling with lapatinib enhanced MRTX849 efficacy in vitro by inhibiting the MAPK and AKT/mTOR pathways. 4NQO-L-AcR upregulated the expression of pan-HERs, and lapatinib treatment re-sensitized 4NQO-L-AcR to MRTX849. In mice, MRTX849 showed a slight anti-tumor effect, but in combination with lapatinib a significant tumor growth delay was observed, but all tumors progressed over time. Histopathology analysis of the TME revealed infiltration of CD8+ T-cells after treatment combination, and these CD8+ T-cells play a key role in MRTX849/lapatinib efficacy. MRTX849/lapatinib treatment upregulated PD-L1 overexpression in both stromal and tumor cells, which presumably suppressed CD8+ T-cells and enabled immune escape and tumor progression. Supplementation of alphaPD-1 prolonged the progression-free survival of 4NQO-L-bearing mice treated with MRTX849/lapatinib. MRTX849/lapatinib treatment delayed tumor growth of 4NQO-L-AcR in mice; however, the percentages of CD8+ T-cells in 4NQO-L-AcR were low, and supplementation of MRTX849/lapatinib with alphaPD-1 did not improve the outcome.
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 Combination therapy of Lapatinib/Letrozole-based protein-vitamin nanoparticles to enhance the therapeutic effectiveness in drug-resistant breast cancer. Colloids Surf B Biointerfaces. 2025 Mar;247:114399.
Ref 4 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 5 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 6 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 7 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 8 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 9 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 10 Artemisia argyi extracts overcome lapatinib resistance via enhancing TMPRSS2 activation in HER2-positive breast cancer. Environ Toxicol. 2024 Jun;39(6):3389-3399.
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.
Ref 12 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 13 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.
Ref 14 DUSP4 enhances therapeutic sensitivity in HER2-positive breast cancer by inhibiting the G6PD pathway and ROS metabolism by interacting with ALDOB. Transl Oncol. 2024 Aug;46:102016.
Ref 15 Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRAS(G12C) inhibitor resistant tumors. Redox Biol. 2024 Dec;78:103419.
Ref 16 Dual inhibition of HERs and PD-1 counteract resistance in KRAS(G12C)-mutant head and neck cancer. J Exp Clin Cancer Res. 2024 Nov 20;43(1):308.

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