Drug Information

Drug (ID: DG00346) and It's Reported Resistant Information
Name
Trastuzumab
Synonyms
Herceptin; Herceptin (TN); Trastuzumab (INN); Trastuzumab (genetical recombination); Trastuzumab (genetical recombination) (JAN); Trastuzumab (ERBB2 mAb inhibitor)
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Indication
In total 2 Indication(s)
Breast cancer [ICD-11: 2C60]
Approved
[1]
Stomach cancer [ICD-11: 2B72]
Application submitted
[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]
Gastric cancer [ICD-11: 2B72]
[4]
Target Erbb2 tyrosine kinase receptor (HER2) ERBB2_HUMAN [1]
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TTD Drug ID
D04WFL
DrugBank ID
DB00072
Type(s) of Resistant Mechanism of This Drug
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  MRAP: Metabolic Reprogramming via Altered Pathways
  RTDM: Regulation by the Disease Microenvironment
  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
Breast cancer [ICD-11: 2C60]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Hepatocyte growth factor receptor (MET) [5]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Breast cancer [ICD-11: 2C60]
The Specified Disease Breast cancer
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 3.91E-01
Fold-change: 2.12E-02
Z-score: 8.60E-01
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell viability Activation hsa05200
MET/PI3K/AKT/mTOR signaling pathway Activation hsa04150
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; RIP assay; Luciferase reporter assay
Experiment for
Drug Resistance		 MTS assay; Transwell assay
Mechanism Description Overexpression of miR-182 reduced trastuzumab resistance in trastuzumab-resistant cells due in part to MET/PI3k/AkT/mTOR signaling pathway inactivation.
Key Molecule: Zinc finger protein 217 (ZNF217) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Breast cancer [ICD-11: 2C60]
The Specified Disease Breast cancer
The Studied Tissue Breast tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 2.02E-41
Fold-change: 9.59E-02
Z-score: 1.50E+01
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
TGF-beta signaling pathway Regulation N.A.
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Lnc-ATB is up-regulated in TR breast cancer tissues and TR SkBR-3 cells. Up-regulation of lnc-ATB account for the trastuzumab resistance and high invasiveness of TR SkBR-3 cells. miR-200c is down-regulated and inverse correlated with lnc-ATB in TR breast cancer tissues and TR SkBR-3 cells. Lnc-ATB functions as a ceRNA by competitively biding miR-200c in TR SkBR-3 cells. Lnc-ATB up-regulates and positive correlates with ZEB1 and ZNF217 levels.
Key Molecule: Myeloid differentiation primary response protein MyD88 (MYD88) [7]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Breast cancer [ICD-11: 2C60]
The Specified Disease Breast cancer
The Studied Tissue Breast tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 7.03E-96
Fold-change: 9.23E-02
Z-score: 2.61E+01
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
NF-kappaB signaling pathway Activation hsa04064
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; TUNEL assay
Mechanism Description AGAP2-AS1 could promote breast cancer growth and trastuzumab resistance by activating the NF-kB signaling pathway and upregulating MyD88 expression.
Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [8]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Breast cancer [ICD-11: 2C60]
The Specified Disease Breast cancer
The Studied Tissue Breast tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 9.93E-08
Fold-change: 6.79E-02
Z-score: 5.40E+00
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
PI3K/AKT signaling pathway Activation hsa04151
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Luciferase reporter assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Insulin-like growth factor-1 receptor (IGF1R) is thought to play a key role in the acquisition of cancer resistance to trastuzumab and other targeted pharmaceuticals. Epigenetic silencing of miR-375 causes the upregulation of IGF1R, which at least partially underlies trastuzumab resistance of breast cancer cells.
Key Molecule: Cyclin-dependent kinase 8 (CDK8) [9]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Breast cancer [ICD-11: 2C60]
The Specified Disease Breast cancer
The Studied Tissue Breast tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.61E-08
Fold-change: 5.12E-02
Z-score: 5.77E+00
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
miR141-3p/CDk8 signaling pathway Inhibition hsa05206
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
HEK293T cells Kidney Homo sapiens (Human) CVCL_0063
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description miR-141-3p could restore the sensitivity to trastuzumab in breast cancer cells by repressing CDk8, which might regulate the phosphorylation levels of SMAD2/SMAD3 via TGF-beta.
Key Molecule: GTPase Hras (HRAS) [26]
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
-
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
|
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: Polyadenylate-binding protein 1 (PABPC1) [18]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Acetylation
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell viability Activation hsa05200
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Long non-coding RNA SNHG14 induces trastuzumab resistance of breast cancer via inducing PABPC1 expression through H3k27 acetylation.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [19]
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 BCL2/Bax apoptosis signaling pathway Activation hsa04210
Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell viability Activation hsa05200
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description Exosomal LncRNA-SNHG14 may induce trastuzumab resistance through inhibiting apoptotic proteins and cell apoptosis via Bcl-2/Bax pathway.
Key Molecule: Transcriptional coactivator YAP1 (YAP1) [14]
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 apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell viability Activation hsa05200
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay; Matrigel Invasion assay
Mechanism Description UCA1 knockdown upregulated miR-18a and downregulated YAP1 in breast cancer cells, restoring sensitivity of breast cancer cells to trastuzumab.
Key Molecule: Phosphatase and tensin homolog (PTEN) [20]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell proliferation Activation hsa05200
mTOR signaling pathway Activation hsa04150
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 Western blot analysis; Flow cytometric assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Down-regulation of LncRNA GAS5 causes trastuzumab resistance in breast cancer.Expression of the LncRNA GAS5 was decreased in trastuzumab-resistant SkBR-3/Tr cells and in breast cancer tissue from trastuzumab-treated patients. GAS5 suppresses cancer proliferation by acting as a molecular sponge for miR-21, leading to the de-repression of phosphatase and tensin homologs (PTEN), the endogenous target of miR-21. Moreover, mTOR activation associated with reduced GAS5 expression was required to suppress PTEN. This work identifies GAS5 as a novel prognostic marker and candidate drug target for HER2-positive breast cancer.
Key Molecule: Programmed cell death protein 4 (PDCD4) [21]
Resistant 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 Inhibition hsa04210
PI3K signaling pathway Activation hsa04151
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description A target prediction analysis coupled with in vitro and in vivo validations revealed that miR-21 levels inversely correlated with the expression of PTEN and PDCD4, which differentially influenced the drug sensitivity of HER2-positive breast cancer cells.miR-21 was able to affect the response to both trastuzumab and chemotherapy, triggering an IL-6/STAT3/NF-kB-mediated signaling loop and activating the PI3k pathway. These findings support the ability of miR-21 signaling to sustain EMT and shape the tumor immune microenvironment in HER2-positive breast cancer.
Key Molecule: Phosphatase and tensin homolog (PTEN) [21]
Resistant 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 Inhibition hsa04210
PI3K signaling pathway Activation hsa04151
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description A target prediction analysis coupled with in vitro and in vivo validations revealed that miR-21 levels inversely correlated with the expression of PTEN and PDCD4, which differentially influenced the drug sensitivity of HER2-positive breast cancer cells.miR-21 was able to affect the response to both trastuzumab and chemotherapy, triggering an IL-6/STAT3/NF-kB-mediated signaling loop and activating the PI3k pathway. These findings support the ability of miR-21 signaling to sustain EMT and shape the tumor immune microenvironment in HER2-positive breast cancer.
Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
TGF-beta signaling pathway Regulation N.A.
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Lnc-ATB is up-regulated in TR breast cancer tissues and TR SkBR-3 cells. Up-regulation of lnc-ATB account for the trastuzumab resistance and high invasiveness of TR SkBR-3 cells. miR-200c is down-regulated and inverse correlated with lnc-ATB in TR breast cancer tissues and TR SkBR-3 cells. Lnc-ATB functions as a ceRNA by competitively biding miR-200c in TR SkBR-3 cells. Lnc-ATB up-regulates and positive correlates with ZEB1 and ZNF217 levels.
Key Molecule: Phosphatase and tensin homolog (PTEN) [2], [22]
Resistant 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 AKT signaling pathway Activation hsa04151
Cell apoptosis Inhibition hsa04210
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
MDA-MB-453 cells Breast Homo sapiens (Human) CVCL_0418
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description PTEN is a tumor suppressing dual phosphatase that antagonizes the function of phosphatidylinositol 3-kinase (PI3k) and negatively regulates AkT activities, and PTEN phosphorylation is a crucial mechanism mediating the anti-tumor effect of trastuzumab by reducing and inhibiting the ErbB2 receptor-bound SRC. Ectopic expression of miR-21 in the previously sensitive cells confers trastuzumab resistance via PTEN inhibition. And miR-221 promotes the invasiveness and trastuzumab resistance of HER2-positive breast cancers by targeting the tumor suppressor gene PTEN.
Key Molecule: Mediator of RNA polymerase II transcription subunit 1 (MED1) [27]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Missense mutation
p.S1179X
 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: Serine-protein kinase ATM (ATM) [27]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Missense mutation
p.I2948F
 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: Platelet-derived growth factor receptor alpha (PDGFRA) [27]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Missense mutation
p.D714E
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT signaling pathway Activation hsa04151
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: Epidermal growth factor receptor (EGFR) [26]
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) [26]
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: Neurogenic locus notch homolog protein 1 (NOTCH1) [26]
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: Neurogenic locus notch homolog protein 1 (NOTCH1) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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: Epidermal growth factor receptor (EGFR) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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) [26]
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: Cadherin-1 (CDH1) [26]
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) [26]
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) [26]
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: Cadherin-1 (CDH1) [26]
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) [26]
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: PI3-kinase alpha (PIK3CA) [28]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Missense mutation
p.E545K (c.1633G>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vivo Model Female athymic nude xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 WST-1 assay
Mechanism Description The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the resistance of Trastuzumab by unusual activation of pro-survival pathway
  Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [10]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Breast cancer [ICD-11: 2C60]
The Specified Disease Breast cancer
The Studied Tissue Breast tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 3.50E-77
Fold-change: 2.67E-01
Z-score: 1.98E+01
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell viability Inhibition hsa05200
miR125b/HER2/Snail1 signaling pathway Regulation N.A.
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Wound-healing assay; Transwell assay
Mechanism Description TINCR, which is transcriptionally activated by H3k27 acetylation, upregulates HER-2 expression by downregulating miR-125b and TINCR promotes trastuzumab resistance-induced EMT by directly targeting Snail-1.
Key Molecule: Zinc finger protein SNAI1 (SNAI1) [10]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Breast cancer [ICD-11: 2C60]
The Specified Disease Breast cancer
The Studied Tissue Breast tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.11E-04
Fold-change: -2.85E-02
Z-score: -3.91E+00
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell viability Inhibition hsa05200
miR125b/HER2/Snail1 signaling pathway Regulation N.A.
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Wound-healing assay; Transwell assay
Mechanism Description TINCR, which is transcriptionally activated by H3k27 acetylation, upregulates HER-2 expression by downregulating miR-125b and TINCR promotes trastuzumab resistance-induced EMT by directly targeting Snail-1.
Key Molecule: hsa-mir-125b [10]
Resistant 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 invasion Activation hsa05200
Cell migration Activation hsa04670
Cell viability Inhibition hsa05200
miR125b/HER2/Snail1 signaling pathway Regulation N.A.
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Wound-healing assay; Transwell assay
Mechanism Description TINCR, which is transcriptionally activated by H3k27 acetylation, upregulates HER-2 expression by downregulating miR-125b and TINCR promotes trastuzumab resistance-induced EMT by directly targeting Snail-1.
Key Molecule: TINCR ubiquitin domain containing (TINCR) [10]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Acetylation
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell viability Inhibition hsa05200
miR125b/HER2/Snail1 signaling pathway Regulation N.A.
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Wound-healing assay; Transwell assay
Mechanism Description TINCR, which is transcriptionally activated by H3k27 acetylation, upregulates HER-2 expression by downregulating miR-125b and TINCR promotes trastuzumab resistance-induced EMT by directly targeting Snail-1.
Key Molecule: AGAP2 antisense RNA 1 (AGAP2-AS1) [7]
Resistant 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 Inhibition hsa04210
Cell colony Activation hsa05200
Cell proliferation Activation hsa05200
NF-kappaB signaling pathway Activation hsa04064
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 MTT assay; TUNEL assay
Mechanism Description AGAP2-AS1 could promote breast cancer growth and trastuzumab resistance by activating the NF-kB signaling pathway and upregulating MyD88 expression.
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: CD36 molecule (CD36) [11]
Metabolic Type Lipid metabolism
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Breast cancer [ICD-11: 2C60]
The Specified Disease Breast cancer
The Studied Tissue Breast tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 7.82E-02
Fold-change: 1.53E-02
Z-score: 1.76E+00
Experimental Note Identified from the Human Clinical Data
In Vivo Model HCC patients Homo Sapiens
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Mechanism Description The main study findings were validated in an independent cohort of HER2+ BC patients enrolled in the randomized, phase II trial NeoSphere. Our results consistently indicate a negative predictive role of a metabolic gene, namely CD36, which is not a classical downstream effector of the HER2 pathway, in HER2+ BC patients receiving trastuzumab-based neoadjuvant therapy.
Key Molecule: NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2) [24]
Metabolic Type Redox metabolism
Resistant Disease HER2-positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model NDUFA4L2-positive patients Homo Sapiens
Experiment for
Molecule Alteration		 Whole-transcriptome expression array
Experiment for
Drug Resistance		 Hazard ratio assay
Mechanism Description Mechanistically, overexpression of NDUFA4L2 facilitated mitochondrial relocalization of HER2 and suppressed ROS production, thus rendering cancer cells more resistant to trastuzumab treatment.
Key Molecule: NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2) [24]
Metabolic Type Redox metabolism
Resistant Disease HER2-positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model NDUFA4L2-negative patients Homo Sapiens
Experiment for
Molecule Alteration		 Whole-transcriptome expression array
Experiment for
Drug Resistance		 Hazard ratio assay
Mechanism Description Mechanistically, overexpression of NDUFA4L2 facilitated mitochondrial relocalization of HER2 and suppressed ROS production, thus rendering cancer cells more resistant to trastuzumab treatment.
Key Molecule: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10 (NDUFA10) [25]
Metabolic Type Glucose metabolism
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model Breast Cancer patients Homo Sapiens
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description The analysis of differentially expressed proteins exhibited the deregulation of energetic metabolism and mitochondrial pathways. A down-regulation of carbohydrate metabolism and up-regulation of mitochondria organization proteins, the tricarboxylic acid cycle, and oxidative phosphorylation, were observed in nRSs. Of note, Complex I-related proteins were increased in this condition and the inhibition by metformin highlighted that their activity is necessary for nRS survival. Furthermore, a correlation analysis showed that overexpression of Complex I proteins NDUFA10 and NDUFS2 was associated with high clinical risk and worse survival for HER2+ BC patients
Key Molecule: NADH dehydrogenase [ubiquinone] iron-sulfur protein 2 (NDUFS2) [25]
Metabolic Type Glucose metabolism
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model Breast Cancer patients Homo Sapiens
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description The analysis of differentially expressed proteins exhibited the deregulation of energetic metabolism and mitochondrial pathways. A down-regulation of carbohydrate metabolism and up-regulation of mitochondria organization proteins, the tricarboxylic acid cycle, and oxidative phosphorylation, were observed in nRSs. Of note, Complex I-related proteins were increased in this condition and the inhibition by metformin highlighted that their activity is necessary for nRS survival. Furthermore, a correlation analysis showed that overexpression of Complex I proteins NDUFA10 and NDUFS2 was associated with high clinical risk and worse survival for HER2+ BC patients
Key Molecule: NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2) [24]
Metabolic Type Redox metabolism
Resistant Disease HER2-positive breast cancer [ICD-11: 2C60.8]
 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
BT474 cells Breast Homo sapiens (Human) CVCL_0179
SK-BR-3 cells Pleural effusion Homo sapiens (Human) CVCL_0033
Parental cells Breast Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Whole-transcriptome expression array
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description Mechanistically, overexpression of NDUFA4L2 facilitated mitochondrial relocalization of HER2 and suppressed ROS production, thus rendering cancer cells more resistant to trastuzumab treatment.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: H19, imprinted maternally expressed transcript (H19) [1]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Higher expression of H19 might lead to trastuzumab resistance in HER2-positive breast cancer patients. High H19 expression was associated with a worse clinical prognosis and a lower PFS.
Key Molecule: hsa-miR-141-3p [9]
Resistant 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 Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
miR141-3p/CDk8 signaling pathway Inhibition hsa05206
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
HEK293T cells Kidney Homo sapiens (Human) CVCL_0063
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description miR-141-3p could restore the sensitivity to trastuzumab in breast cancer cells by repressing CDk8, which might regulate the phosphorylation levels of SMAD2/SMAD3 via TGF-beta.
Key Molecule: Small nucleolar RNA host gene 14 (SNHG14) [18]
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 apoptosis Inhibition hsa04210
Cell colony Activation hsa05200
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell viability Activation hsa05200
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Long non-coding RNA SNHG14 induces trastuzumab resistance of breast cancer via inducing PABPC1 expression through H3k27 acetylation.
Key Molecule: Small nucleolar RNA host gene 14 (SNHG14) [19]
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 BCL2/Bax apoptosis signaling pathway Activation hsa04210
Cell invasion Inhibition hsa05200
Cell metabolism Inhibition hsa01100
Cell migration Inhibition hsa04670
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description Exosomal LncRNA-SNHG14 may induce trastuzumab resistance through inhibiting apoptotic proteins and cell apoptosis via Bcl-2/Bax pathway.
Key Molecule: hsa-mir-182 [5]
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 autophagy Inhibition hsa04140
MET/PI3K/AKT/mTOR signaling pathway Activation hsa04150
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTS assay; Transwell assay
Mechanism Description Overexpression of miR-182 reduced trastuzumab resistance in trastuzumab-resistant cells due in part to MET/PI3k/AkT/mTOR signaling pathway inactivation.
Key Molecule: Urothelial cancer associated 1 (UCA1) [14]
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 apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell viability Activation hsa05200
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay; Matrigel Invasion assay
Mechanism Description UCA1 knockdown upregulated miR-18a and downregulated YAP1 in breast cancer cells, restoring sensitivity of breast cancer cells to trastuzumab.
Key Molecule: Growth arrest specific 5 (GAS5) [20]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell proliferation Activation hsa05200
mTOR signaling pathway Activation hsa04150
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Down-regulation of LncRNA GAS5 causes trastuzumab resistance in breast cancer.Expression of the LncRNA GAS5 was decreased in trastuzumab-resistant SkBR-3/Tr cells and in breast cancer tissue from trastuzumab-treated patients. GAS5 suppresses cancer proliferation by acting as a molecular sponge for miR-21, leading to the de-repression of phosphatase and tensin homologs (PTEN), the endogenous target of miR-21. Moreover, mTOR activation associated with reduced GAS5 expression was required to suppress PTEN. This work identifies GAS5 as a novel prognostic marker and candidate drug target for HER2-positive breast cancer.
Key Molecule: hsa-mir-21 [21]
Resistant 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 Inhibition hsa04210
PI3K signaling pathway Activation hsa04151
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description A target prediction analysis coupled with in vitro and in vivo validations revealed that miR-21 levels inversely correlated with the expression of PTEN and PDCD4, which differentially influenced the drug sensitivity of HER2-positive breast cancer cells.miR-21 was able to affect the response to both trastuzumab and chemotherapy, triggering an IL-6/STAT3/NF-kB-mediated signaling loop and activating the PI3k pathway. These findings support the ability of miR-21 signaling to sustain EMT and shape the tumor immune microenvironment in HER2-positive breast cancer.
Key Molecule: Long non-protein coding RNA (Lnc-ATB) [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
TGF-beta signaling pathway Regulation N.A.
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Lnc-ATB is up-regulated in TR breast cancer tissues and TR SkBR-3 cells. Up-regulation of lnc-ATB account for the trastuzumab resistance and high invasiveness of TR SkBR-3 cells. miR-200c is down-regulated and inverse correlated with lnc-ATB in TR breast cancer tissues and TR SkBR-3 cells. Lnc-ATB functions as a ceRNA by competitively biding miR-200c in TR SkBR-3 cells. Lnc-ATB up-regulates and positive correlates with ZEB1 and ZNF217 levels.
Key Molecule: hsa-mir-200c [6]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
TGF-beta signaling pathway Regulation N.A.
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Lnc-ATB is up-regulated in TR breast cancer tissues and TR SkBR-3 cells. Up-regulation of lnc-ATB account for the trastuzumab resistance and high invasiveness of TR SkBR-3 cells. miR-200c is down-regulated and inverse correlated with lnc-ATB in TR breast cancer tissues and TR SkBR-3 cells. Lnc-ATB functions as a ceRNA by competitively biding miR-200c in TR SkBR-3 cells. Lnc-ATB up-regulates and positive correlates with ZEB1 and ZNF217 levels.
Key Molecule: hsa-miR-542-3p [3]
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 apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
MCF7/HER2 cells Breast Homo sapiens (Human) CVCL_0U80
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Trastuzumab induced miRNA 542 3p expression in SkBR3 and MCF7/Her2 cells. Furthermore, knockdown of miRNA 542 3p in the two cell lines resulted in decreased drug sensitivity to trastuzumab and cell apoptosis. The blockage of G1/S checkpoint by trastuzumab was rescued as well. miRNA 542 3p knockdown also activated the phosphatidylinositol 3 kinase (PI3k) Akt pathway, while LY294002 reversed the effect of miRNA 542 3p knockdown. In summary, the results suggested that miRNA 542 3p downregulation may contribute to the trastuzumab resistance in breast cancer via, at least in part, the PI3k akt pathway.
Key Molecule: hsa-mir-375 [8]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
PI3K/AKT signaling pathway Activation hsa04151
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Insulin-like growth factor-1 receptor (IGF1R) is thought to play a key role in the acquisition of cancer resistance to trastuzumab and other targeted pharmaceuticals. Epigenetic silencing of miR-375 causes the upregulation of IGF1R, which at least partially underlies trastuzumab resistance of breast cancer cells.
Key Molecule: hsa-mir-221 [22]
Resistant 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 Inhibition hsa04210
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-221 promotes the invasiveness and trastuzumab resistance of HER2-positive breast cancers by targeting the tumor suppressor gene PTEN.
Key Molecule: hsa-mir-210 [23]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model BT474 cells Breast Homo sapiens (Human) CVCL_0179
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Clonogenic assay
Mechanism Description The function of miR-210, which is directly regulated by hypoxia-inducible factor 1-alpha, may also depend on cancer type. miR-210 inhibits apoptosis, bypasses cell-cycle arrest, and promotes cancer cell survival when overexpressed, but when underexpressed, as it is in esophageal squamous cell carcinoma, it represses the initiation of tumor growth by inducing cell death and cell-cycle arrest.
Key Molecule: hsa-mir-21 [2]
Resistant 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 AKT signaling pathway Activation hsa04151
Cell proliferation Activation hsa05200
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
MDA-MB-453 cells Breast Homo sapiens (Human) CVCL_0418
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR; Northern blotting analysis
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description PTEN is a tumor suppressing dual phosphatase that antagonizes the function of phosphatidylinositol 3-kinase (PI3k) and negatively regulates AkT activities, and PTEN phosphorylation is a crucial mechanism mediating the anti-tumor effect of trastuzumab by reducing and inhibiting the ErbB2 receptor-bound SRC. Ectopic expression of miR-21 in the previously sensitive cells confers trastuzumab resistance via PTEN inhibition.
Key Molecule: TINCR ubiquitin domain containing (TINCR) [10]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
In Vitro Model Lunet cells hepato Homo sapiens (Human) CVCL_U459
Pseudomonas aeruginosa strain B-730P/17 287
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Activation of LncRNA TINCR by H3K27 acetylation promotes trastuzumab resistance and epithelial-mesenchymal transition by targeting MicroRNA-125b in breast cancer.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Ribosomal protein S6 (RPS6) [13]
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Breast cancer [ICD-11: 2C60]
The Specified Disease Breast cancer
The Studied Tissue Breast tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 6.31E-19
Fold-change: -2.69E-02
Z-score: -9.24E+00
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation PI3K/AKT/mTOR signaling pathway Inhibition hsa04151
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
JIMT-1 cells Breast Homo sapiens (Human) CVCL_2077
Experiment for
Molecule Alteration		 Western blot analysis; Luciferase reporter assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR129-5p might inhibit trastuzumab resistance through downregulating rpS6 in Her-2-positive breast cancer cells, thus inactivating the PI3k/Akt/mTOR/ rpS6 pathway.
Key Molecule: Transcriptional coactivator YAP1 (YAP1) [14]
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Breast cancer [ICD-11: 2C60]
The Specified Disease Breast cancer
The Studied Tissue Breast tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.58E-47
Fold-change: -1.19E-01
Z-score: -1.62E+01
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell viability Inhibition hsa05200
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay; Matrigel Invasion assay
Mechanism Description UCA1 knockdown upregulated miR-18a and downregulated YAP1 in breast cancer cells, restoring sensitivity of breast cancer cells to trastuzumab.
Key Molecule: Epidermal growth factor receptor (EGFR) [15]
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Breast cancer [ICD-11: 2C60]
The Specified Disease Breast cancer
The Studied Tissue Breast tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.04E-65
Fold-change: -1.82E-01
Z-score: -2.10E+01
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Colcount colony counter assay
Mechanism Description miR-7 suppression of HER2deta16 oncogenic activity is mediated through inactivation of Src kinase and suppression of EGFR expression implies that targeting these pathways would also suppress HER2deta16 tumorigenesis. HER2deta16 suppresses expression of the miR-7 tumor suppressor and reestablished miR-7 expression significantly inhibits HER2deta16 mediated tumor cell proliferation and migration and miR-7 sensitizes HER2deta16 expressing cells to trastuzumab treatment.
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [29]
Sensitive Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell proliferation Inhibition hsa05200
HER2 signaling pathway Activation hsa04012
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
Experiment for
Molecule Alteration		 Western blot analysis; RT-qPCR
Experiment for
Drug Resistance		 WST1 assay
Mechanism Description miR-770-5p overexpression downregulated HER2 and increased the effect of trastuzumab.
Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [30]
Sensitive 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 invasion Inhibition hsa05200
TGF-Beta/ZEB1 signaling pathway Inhibition hsa04350
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-200c, which was the most significantly downregulated miRNA in trastuzumab-resistant cells, restored trastuzumab sensitivity and suppressed invasion of breast cancer cells by concurrently targeting ZNF217, a transcriptional activator of TGF-beta, and ZEB1, a known mediator of TGF-beta signaling. Restoration of miR-200c, silencing of ZEB1 or ZNF217 or blockade of TGF-beta signaling increased trastuzumab sensitivity and suppressed invasiveness of breast cancer cells.
Key Molecule: Zinc finger protein 217 (ZNF217) [30]
Sensitive 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 invasion Inhibition hsa05200
TGF-Beta/ZEB1 signaling pathway Inhibition hsa04350
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-200c, which was the most significantly downregulated miRNA in trastuzumab-resistant cells, restored trastuzumab sensitivity and suppressed invasion of breast cancer cells by concurrently targeting ZNF217, a transcriptional activator of TGF-beta, and ZEB1, a known mediator of TGF-beta signaling. Restoration of miR-200c, silencing of ZEB1 or ZNF217 or blockade of TGF-beta signaling increased trastuzumab sensitivity and suppressed invasiveness of breast cancer cells.
Key Molecule: hsa-miR-770-5p [33]
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
Cell Pathway Regulation EGFR/HER2/IGF1R signaling pathway Regulation N.A.
In Vitro Model BT-474 cells Breast Homo sapiens (Human) CVCL_0179
SK-BR-3 cells Pleural effusion Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 Cell proliferation assay
Mechanism Description The effect of miR-770-5p on the EGFR/HER2/IGF1R crosstalk signaling. In general, tumorigenesis of breast cancer is assumed to be associated with the PI3K and MAPK pathways and signaling these pathway complex has critical roles in cell proliferation in HER2 amplified cells. Trastuzumab can block this signaling, either by inhibiting the activity of EGFR and HER2 kinases directly or through HER2 binding at the cell surface. miR-770-5p can reduce dissociation of receptor crosstalk signaling, which increases its activity.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-miR-770-5p [29]
Sensitive Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell proliferation Inhibition hsa05200
HER2 signaling pathway Activation hsa04012
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 WST1 assay
Mechanism Description miR-770-5p overexpression downregulated HER2 and increased the effect of trastuzumab.
Key Molecule: hsa-miR-129-5p [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 PI3K/AKT/mTOR signaling pathway Inhibition hsa04151
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
JIMT-1 cells Breast Homo sapiens (Human) CVCL_2077
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR129-5p might inhibit trastuzumab resistance through downregulating rpS6 in Her-2-positive breast cancer cells, thus inactivating the PI3k/Akt/mTOR/ rpS6 pathway.
Key Molecule: hsa-mir-18a [14]
Sensitive 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 apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell viability Inhibition hsa05200
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay; Matrigel Invasion assay
Mechanism Description UCA1 knockdown upregulated miR-18a and downregulated YAP1 in breast cancer cells, restoring sensitivity of breast cancer cells to trastuzumab.
Key Molecule: Urothelial cancer associated 1 (UCA1) [14]
Sensitive 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 apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell viability Inhibition hsa05200
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay; Matrigel Invasion assay
Mechanism Description UCA1 knockdown upregulated miR-18a and downregulated YAP1 in breast cancer cells, restoring sensitivity of breast cancer cells to trastuzumab.
Key Molecule: hsa-mir-7 [15]
Sensitive 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 invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 Colcount colony counter assay
Mechanism Description miR-7 suppression of HER2deta16 oncogenic activity is mediated through inactivation of Src kinase and suppression of EGFR expression implies that targeting these pathways would also suppress HER2deta16 tumorigenesis. HER2deta16 suppresses expression of the miR-7 tumor suppressor and reestablished miR-7 expression significantly inhibits HER2deta16 mediated tumor cell proliferation and migration and miR-7 sensitizes HER2deta16 expressing cells to trastuzumab treatment.
Key Molecule: hsa-mir-200c [30]
Sensitive 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 apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
TGF-Beta/ZEB1 signaling pathway Inhibition hsa04350
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-200c, which was the most significantly downregulated miRNA in trastuzumab-resistant cells, restored trastuzumab sensitivity and suppressed invasion of breast cancer cells by concurrently targeting ZNF217, a transcriptional activator of TGF-beta, and ZEB1, a known mediator of TGF-beta signaling. Restoration of miR-200c, silencing of ZEB1 or ZNF217 or blockade of TGF-beta signaling increased trastuzumab sensitivity and suppressed invasiveness of breast cancer cells.
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Dual specificity phosphatase 4 (DUSP4) [31]
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 HER2-positive BC.
Key Molecule: Dual specificity phosphatase 4 (DUSP4) [31]
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 HER3-positive BC.
  Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: hnRNP A2/B1 (HNRNPA2B1) [32]
Sensitive 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 apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; TUNEL assay; Flow cytometry assay
Mechanism Description Exosomal AGAP2-AS1 expression was upregulated by hnRNPA2B1 overexpression and suppressed by hnRNPA2B1 knockdown in SkBR-3R cells while knockdown of AGAP2-AS1 resensitized trastuzumab resistance in breast cancer cells.
Key Molecule: AGAP2 antisense RNA 1 (AGAP2-AS1) [32]
Sensitive 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 apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
In Vitro Model SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
BT474 cells Breast Homo sapiens (Human) CVCL_0179
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; TUNEL assay; Flow cytometry assay
Mechanism Description Exosomal AGAP2-AS1 expression was upregulated by hnRNPA2B1 overexpression and suppressed by hnRNPA2B1 knockdown in SkBR-3R cells while knockdown of AGAP2-AS1 resensitized trastuzumab resistance in breast cancer cells.
Gastric cancer [ICD-11: 2B72]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: F-box/WD repeat-containing protein 7 (FBXW7) [12]
Resistant 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: 1.37E-01
Fold-change: -1.86E-02
Z-score: -2.10E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
miR223/FBXW7 signaling pathway Regulation N.A.
In Vitro Model NCI-N87 cells Gastric Homo sapiens (Human) CVCL_1603
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
NUGC3 cells Gastric Homo sapiens (Human) CVCL_1612
NUGC4 cells Gastric Homo sapiens (Human) CVCL_3082
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description Overexpression of miR-223 decreased FBXW7 expression and the sensitivity of GC cells to trastuzumab, while suppression of miR-223 restored FBXW7 expression and the sensitivity of GC cells to trastuzumab.
Key Molecule: Phosphatase and tensin homolog (PTEN) [4]
Resistant Disease Gastric cancer [ICD-11: 2B72.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
miR21/PTEN signaling pathway Activation hsa05206
In Vitro Model NCI-N87 cells Gastric Homo sapiens (Human) CVCL_1603
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
NUGC4 cells Gastric Homo sapiens (Human) CVCL_3082
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description The miR-21/PTEN pathway regulated the sensitivity of HER2-positive GC cell lines to trastuzumab through modulation apoptosis.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-223 [12]
Resistant 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 apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
miR223/FBXW7 signaling pathway Regulation N.A.
In Vitro Model NCI-N87 cells Gastric Homo sapiens (Human) CVCL_1603
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
NUGC3 cells Gastric Homo sapiens (Human) CVCL_1612
NUGC4 cells Gastric Homo sapiens (Human) CVCL_3082
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description Overexpression of miR-223 decreased FBXW7 expression and the sensitivity of GC cells to trastuzumab, while suppression of miR-223 restored FBXW7 expression and the sensitivity of GC cells to trastuzumab.
Key Molecule: hsa-mir-21 [4]
Resistant 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 apoptosis Inhibition hsa04210
miR21/PTEN signaling pathway Activation hsa05206
In Vitro Model NCI-N87 cells Gastric Homo sapiens (Human) CVCL_1603
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
NUGC4 cells Gastric Homo sapiens (Human) CVCL_3082
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description The miR-21/PTEN pathway regulated the sensitivity of HER2-positive GC cell lines to trastuzumab through modulation apoptosis.
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: GATA-binding protein 6 (GATA6) [16]
Metabolic Type Glucose metabolism
Resistant Disease Gastric adenocarcinoma [ICD-11: 2B72.0]
 Disease Info 
Molecule Alteration Activity
activation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NCI N87R cells Stomach Homo sapiens (Human) CVCL_1603
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Taken together, these findings demonstrate that GATA6 is involved in metabolism reprogramming which might contribute to trastuzumab resistance in gastric cancer.
Key Molecule: GATA-binding protein 6 (GATA6) [16]
Metabolic Type Glucose metabolism
Resistant Disease Gastric adenocarcinoma [ICD-11: 2B72.0]
 Disease Info 
Molecule Alteration Activity
activation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NCI N87R/deltaGATA6 cells Stomach Homo sapiens (Human) CVCL_1603
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Taken together, these findings demonstrate that GATA7 is involved in metabolism reprogramming which might contribute to trastuzumab resistance in gastric cancer.
Key Molecule: GATA-binding protein 6 (GATA6) [16]
Metabolic Type Glucose metabolism
Resistant Disease Gastric adenocarcinoma [ICD-11: 2B72.0]
 Disease Info 
Molecule Alteration Activity
activation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MKN45R cells Stomach Homo sapiens (Human) CVCL_0434
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Taken together, these findings demonstrate that GATA8 is involved in metabolism reprogramming which might contribute to trastuzumab resistance in gastric cancer.
Key Molecule: GATA-binding protein 6 (GATA6) [16]
Metabolic Type Glucose metabolism
Resistant Disease Gastric adenocarcinoma [ICD-11: 2B72.0]
 Disease Info 
Molecule Alteration Activity
activation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MKN45R/deltaGATA6 cells Stomach Homo sapiens (Human) CVCL_0434
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Taken together, these findings demonstrate that GATA9 is involved in metabolism reprogramming which might contribute to trastuzumab resistance in gastric cancer.
Key Molecule: Metastasis associated in colon cancer protein 1 (MACC1) [17]
Metabolic Type Glucose metabolism
Resistant Disease HER2-positive advanced 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 Human papillomavirus infection Activation hsa05165
In Vitro Model BGC823 cells Gastric Homo sapiens (Human) CVCL_3360
NCI-N87 with high HER2 expressions cells Stomach Homo sapiens (Human) CVCL_1603
MkN28 cells Gastric Homo sapiens (Human) CVCL_1416
MKN45 parental cells with high HER2 expressions Stomach Homo sapiens (Human) CVCL_0434
SGC-7901 cells Gastric Homo sapiens (Human) CVCL_0520
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Overexpression of MACC1-induced trastuzumab resistance, enhanced the Warburg effect, and activated the PI3K/AKT signaling pathway, while downregulation of MACC1 presented the opposite effects.
Key Molecule: Metastasis associated in colon cancer protein 1 (MACC1) [17]
Metabolic Type Glucose metabolism
Resistant Disease HER2-positive advanced 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 Human papillomavirus infection Activation hsa05165
In Vivo Model BALB/c nude mouse xenograft model using NCI-N87 MACC1-overexpressing Mice
Experiment for
Drug Resistance		 Tumor volume assay
Mechanism Description Overexpression of MACC1-induced trastuzumab resistance, enhanced the Warburg effect, and activated the PI3K/AKT signaling pathway, while downregulation of MACC1 presented the opposite effects.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Metastasis associated in colon cancer protein 1 (MACC1) [17]
Metabolic Type Glucose metabolism
Sensitive Disease HER2-positive advanced gastric cancer [ICD-11: 2B72.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Human papillomavirus infection Activation hsa05165
In Vitro Model MKN45 cells Liver Homo sapiens (Human) CVCL_0434
NCI-N87 cells Gastric Homo sapiens (Human) CVCL_1603
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description Overexpression of MACC1-induced trastuzumab resistance, enhanced the Warburg effect, and activated the PI3K/AKT signaling pathway, while downregulation of MACC1 presented the opposite effects.
Key Molecule: Metastasis associated in colon cancer protein 1 (MACC1) [17]
Metabolic Type Glucose metabolism
Sensitive Disease HER2-positive advanced 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 Human papillomavirus infection Activation hsa05165
In Vivo Model BALB/c nude mouse xenograft model using NCI-N87 MACC1-silenced Mice
Experiment for
Drug Resistance		 Tumor volume assay
Mechanism Description Overexpression of MACC1-induced trastuzumab resistance, enhanced the Warburg effect, and activated the PI3K/AKT signaling pathway, while downregulation of MACC1 presented the opposite effects.
References
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Ref 2 Up-regulation of miR-21 mediates resistance to trastuzumab therapy for breast cancer. J Biol Chem. 2011 May 27;286(21):19127-37. doi: 10.1074/jbc.M110.216887. Epub 2011 Apr 6.
Ref 3 MiRNA 542 3p downregulation promotes trastuzumab resistance in breast cancer cells via AKT activation. Oncol Rep. 2015 Mar;33(3):1215-20. doi: 10.3892/or.2015.3713. Epub 2015 Jan 13.
Ref 4 The microRNA-21/PTEN pathway regulates the sensitivity of HER2-positive gastric cancer cells to trastuzumab. Ann Surg Oncol. 2014 Jan;21(1):343-50. doi: 10.1245/s10434-013-3325-7. Epub 2013 Oct 24.
Ref 5 miR-182 regulates trastuzumab resistance by targeting MET in breast cancer cells. Cancer Gene Ther. 2019 Feb;26(1-2):1-10. doi: 10.1038/s41417-018-0031-4. Epub 2018 Jun 21.
Ref 6 LncRNA-ATB promotes trastuzumab resistance and invasion-metastasis cascade in breast cancer. Oncotarget. 2015 May 10;6(13):11652-63. doi: 10.18632/oncotarget.3457.
Ref 7 SP1-induced lncRNA AGAP2-AS1 expression promotes chemoresistance of breast cancer by epigenetic regulation of MyD88. J Exp Clin Cancer Res. 2018 Aug 29;37(1):202. doi: 10.1186/s13046-018-0875-3.
Ref 8 Epigenetic silencing of miR-375 induces trastuzumab resistance in HER2-positive breast cancer by targeting IGF1R. BMC Cancer. 2014 Feb 26;14:134. doi: 10.1186/1471-2407-14-134.
Ref 9 The microRNA-141-3p/ CDK8 pathway regulates the chemosensitivity of breast cancer cells to trastuzumab. J Cell Biochem. 2019 Aug;120(8):14095-14106. doi: 10.1002/jcb.28685. Epub 2019 May 14.
Ref 10 Activation of LncRNA TINCR by H3K27 acetylation promotes Trastuzumab resistance and epithelial-mesenchymal transition by targeting MicroRNA-125b in breast Cancer. Mol Cancer. 2019 Jan 8;18(1):3. doi: 10.1186/s12943-018-0931-9.
Ref 11 Predictive Role of CD36 Expression in HER2-Positive Breast Cancer Patients Receiving Neoadjuvant Trastuzumab. J Natl Cancer Inst. 2022 Dec 8;114(12):1720-1727.
Ref 12 The sensitivity of gastric cancer to trastuzumab is regulated by the miR-223/FBXW7 pathway. Int J Cancer. 2015 Apr 1;136(7):1537-45. doi: 10.1002/ijc.29168. Epub 2014 Sep 11.
Ref 13 MiR-129-5p Sensitizes the Response of Her-2 Positive Breast Cancer to Trastuzumab by Reducing Rps6. Cell Physiol Biochem. 2017;44(6):2346-2356. doi: 10.1159/000486122. Epub 2017 Dec 15.
Ref 14 Long non-coding RNA UCA1 desensitizes breast cancer cells to trastuzumab by impeding miR-18a repression of Yes-associated protein 1. Biochem Biophys Res Commun. 2018 Feb 19;496(4):1308-1313. doi: 10.1016/j.bbrc.2018.02.006. Epub 2018 Feb 7.
Ref 15 MicroRNA-7 inhibits multiple oncogenic pathways to suppress HER2 Delta 16 mediated breast tumorigenesis and reverse trastuzumab resistance. PLoS One. 2014 Dec 22;9(12):e114419. doi: 10.1371/journal.pone.0114419. eCollection 2014.
Ref 16 Metabolic pathways underlying GATA6 regulating Trastuzumab resistance in Gastric Cancer cells based on untargeted metabolomics. Int J Med Sci. 2020 Oct 23;17(18):3146-3164.
Ref 17 A new mechanism of trastuzumab resistance in gastric cancer: MACC1 promotes the Warburg effect via activation of the PI3K/AKT signaling pathway. J Hematol Oncol. 2016 Aug 31;9(1):76.
Ref 18 Long non-coding RNA SNHG14 induces trastuzumab resistance of breast cancer via regulating PABPC1 expression through H3K27 acetylation. J Cell Mol Med. 2018 Oct;22(10):4935-4947. doi: 10.1111/jcmm.13758. Epub 2018 Jul 31.
Ref 19 Exosome-mediated transfer of lncRNA SNHG14 promotes trastuzumab chemoresistance in breast cancer. Int J Oncol. 2018 Sep;53(3):1013-1026. doi: 10.3892/ijo.2018.4467. Epub 2018 Jul 3.
Ref 20 Downregulation of LncRNA GAS5 causes trastuzumab resistance in breast cancer. Oncotarget. 2016 May 10;7(19):27778-86. doi: 10.18632/oncotarget.8413.
Ref 21 MicroRNA-21 links epithelial-to-mesenchymal transition and inflammatory signals to confer resistance to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer patients. Oncotarget. 2015 Nov 10;6(35):37269-80. doi: 10.18632/oncotarget.5495.
Ref 22 MiR-221 promotes trastuzumab-resistance and metastasis in HER2-positive breast cancers by targeting PTEN. BMB Rep. 2014 May;47(5):268-73. doi: 10.5483/bmbrep.2014.47.5.165.
Ref 23 Plasma microRNA 210 levels correlate with sensitivity to trastuzumab and tumor presence in breast cancer patients. Cancer. 2012 May 15;118(10):2603-14. doi: 10.1002/cncr.26565. Epub 2011 Oct 5.
Ref 24 NDUFA4L2 promotes trastuzumab resistance in HER2-positive breast cancer. Ther Adv Med Oncol. 2021 Jun 30;13:17588359211027836.
Ref 25 Proteomic Characterization of a 3D HER2+ Breast Cancer Model Reveals the Role of Mitochondrial Complex I in Acquired Resistance to Trastuzumab. Int J Mol Sci. 2024 Jul 5;25(13):7397.
Ref 26 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 27 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 28 NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutationsCancer Res. 2008 Oct 1;68(19):8022-30. doi: 10.1158/0008-5472.CAN-08-1385.
Ref 29 Involvement of miR-770-5p in trastuzumab response in HER2 positive breast cancer cells. PLoS One. 2019 Apr 22;14(4):e0215894. doi: 10.1371/journal.pone.0215894. eCollection 2019.
Ref 30 MiR-200c suppresses TGF-Beta signaling and counteracts trastuzumab resistance and metastasis by targeting ZNF217 and ZEB1 in breast cancer. Int J Cancer. 2014 Sep 15;135(6):1356-68. doi: 10.1002/ijc.28782. Epub 2014 Mar 3.
Ref 31 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 32 Increased Expression of Exosomal AGAP2-AS1 (AGAP2 Antisense RNA 1) In Breast Cancer Cells Inhibits Trastuzumab-Induced Cell Cytotoxicity. Med Sci Monit. 2019 Mar 26;25:2211-2220. doi: 10.12659/MSM.915419.
Ref 33 miR-770-5p-induced cellular switch to sensitize trastuzumab resistant breast cancer cells targeting HER2/EGFR/IGF1R bidirectional crosstalk. Turk J Biol. 2024 Feb 5;48(2):153-162.

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