Molecule Information

General Information of the Molecule (ID: Mol00597)

• Name: Receptor tyrosine-protein kinase erbB-3 (ERBB3) ,Homo sapiens
• Synonyms: Proto-oncogene-like protein c-ErbB-3; Tyrosine kinase-type cell surface receptor HER3; HER3
• Molecule Type: Protein
• Gene Name: ERBB3
• Gene ID: 2065
• Location: chr12:56076799-56103505[+]
• Sequence:
  MRANDALQVLGLLFSLARGSEVGNSQAVCPGTLNGLSVTGDAENQYQTLYKLYERCEVVM
  GNLEIVLTGHNADLSFLQWIREVTGYVLVAMNEFSTLPLPNLRVVRGTQVYDGKFAIFVM
  LNYNTNSSHALRQLRLTQLTEILSGGVYIEKNDKLCHMDTIDWRDIVRDRDAEIVVKDNG
  RSCPPCHEVCKGRCWGPGSEDCQTLTKTICAPQCNGHCFGPNPNQCCHDECAGGCSGPQD
  TDCFACRHFNDSGACVPRCPQPLVYNKLTFQLEPNPHTKYQYGGVCVASCPHNFVVDQTS
  CVRACPPDKMEVDKNGLKMCEPCGGLCPKACEGTGSGSRFQTVDSSNIDGFVNCTKILGN
  LDFLITGLNGDPWHKIPALDPEKLNVFRTVREITGYLNIQSWPPHMHNFSVFSNLTTIGG
  RSLYNRGFSLLIMKNLNVTSLGFRSLKEISAGRIYISANRQLCYHHSLNWTKVLRGPTEE
  RLDIKHNRPRRDCVAEGKVCDPLCSSGGCWGPGPGQCLSCRNYSRGGVCVTHCNFLNGEP
  REFAHEAECFSCHPECQPMEGTATCNGSGSDTCAQCAHFRDGPHCVSSCPHGVLGAKGPI
  YKYPDVQNECRPCHENCTQGCKGPELQDCLGQTLVLIGKTHLTMALTVIAGLVVIFMMLG
  GTFLYWRGRRIQNKRAMRRYLERGESIEPLDPSEKANKVLARIFKETELRKLKVLGSGVF
  GTVHKGVWIPEGESIKIPVCIKVIEDKSGRQSFQAVTDHMLAIGSLDHAHIVRLLGLCPG
  SSLQLVTQYLPLGSLLDHVRQHRGALGPQLLLNWGVQIAKGMYYLEEHGMVHRNLAARNV
  LLKSPSQVQVADFGVADLLPPDDKQLLYSEAKTPIKWMALESIHFGKYTHQSDVWSYGVT
  VWELMTFGAEPYAGLRLAEVPDLLEKGERLAQPQICTIDVYMVMVKCWMIDENIRPTFKE
  LANEFTRMARDPPRYLVIKRESGPGIAPGPEPHGLTNKKLEEVELEPELDLDLDLEAEED
  NLATTTLGSALSLPVGTLNRPRGSQSLLSPSSGYMPMNQGNLGESCQESAVSGSSERCPR
  PVSLHPMPRGCLASESSEGHVTGSEAELQEKVSMCRSRSRSRSPRPRGDSAYHSQRHSLL
  TPVTPLSPPGLEEEDVNGYVMPDTHLKGTPSSREGTLSSVGLSSVLGTEEEDEDEEYEYM
  NRRRRHSPPHPPRPSSLEELGYEYMDVGSDLSASLGSTQSCPLHPVPIMPTAGTTPDEDY
  EYMNRQRDGGGPGGDYAAMGACPASEQGYEEMRAFQGPGHQAPHVHYARLKTLRSLEATD
  SAFDNPDYWHSRLFPKANAQRT
• 3D-structure: PDB ID: 5O4O; Classification: Immune system; Method: X-ray diffraction; Resolution: 3.40 Å
• Function: Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins. Binds to neuregulin-1 (NRG1) and is activated by it; ligand-binding increases phosphorylation on tyrosine residues and promotes its association with the p85 subunit of phosphatidylinositol 3-kinase. May also be activated by CSPG5. Involved in the regulation of myeloid cell differentiation.
• Uniprot ID: ERBB3_HUMAN
• Ensembl ID: ENSG00000065361
• HGNC ID: HGNC:3431

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Docetaxel

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [ICD-11: 2C60.3] [1]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The reintroduction of miR-205 is shown to inhibit cell proliferation and clonogenic potential, and increase the sensitivity of MCF-7 and MDA-MB-231 cells to docetaxel. miR-205 also shows a synergistic effect with docetaxel in vivo.

Gefitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [ICD-11: 2C60.3] [2]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Gefitinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Luciferase target assay
• Experiment for Drug Resistance: Fluorescence-activated cell sorting assay
• Mechanism Description: The activation of the PI3k/Akt survival pathway, so critically important in tumorigenesis, is for the most part driven through phosphorylation of the kinase-inactive member HER3. miR-205, negatively regulating HER3, is able to inhibit breast cancer cell proliferation and improves the response to specific targeted therapies. The reintroduction of miR-205 in SkBr3 cells inhibits their clonogenic potential and increases the responsiveness to tyrosine-kinase inhibitors Gefitinib and Lapatinib, abrogating the HER3-mediated resistance and restoring a potent proapoptotic activity.

Lapatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [ICD-11: 2C60.3] [3]

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

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [ICD-11: 2C60.3] [2]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Lapatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Luciferase target assay
• Experiment for Drug Resistance: Fluorescence-activated cell sorting assay
• Mechanism Description: The activation of the PI3k/Akt survival pathway, so critically important in tumorigenesis, is for the most part driven through phosphorylation of the kinase-inactive member HER3. miR-205, negatively regulating HER3, is able to inhibit breast cancer cell proliferation and improves the response to specific targeted therapies. The reintroduction of miR-205 in SkBr3 cells inhibits their clonogenic potential and increases the responsiveness to tyrosine-kinase inhibitors Gefitinib and Lapatinib, abrogating the HER3-mediated resistance and restoring a potent proapoptotic activity.

Selpercatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: ret-aberrant cancers [ICD-11: 2D4Z] [4]

• Resistant Disease: ret-aberrant cancers [ICD-11: 2D4Z]
• Resistant Drug: Selpercatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: YAP-HER3 signaling pathway; Regulation; N.A.
• In Vitro Model: LC2/ad cells; Pleural effusion; Homo sapiens (Human); CVCL_1373
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vivo Model: Severe combined immunodeficiency mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay; RT-PCR; RNA sequencing assay; Phospho-receptor tyrosine kinase antibody arrays assay; Chromatin immunoprecipitation assay; Luciferase reporter assay
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/tea domain inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pretreatment YAP expression in clinical specimens obtained from patients with RET fusion-positive lung cancer was associated with poor RET-TKI treatment outcomes.The YAP-HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment.

Preclinical Drug(s) 2 drug(s) in total

Anti-HER3 mAbs

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Anti-HER3 mAbs
• Molecule Alteration: Missense mutation; p.G284R (c.850G>A)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.G284R (c.850G>A) in gene ERBB3 cause the sensitivity of anti-HER3 mAbs by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Anti-HER3 mAbs
• Molecule Alteration: Missense mutation; p.P262H (c.785C>A)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.P262H (c.785C>A) in gene ERBB3 cause the sensitivity of anti-HER3 mAbs by aberration of the drug's therapeutic target

PI3K pathway inhibitors/MEK inhibitors

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PI3K pathway inhibitors/MEK inhibitors
• Molecule Alteration: Missense mutation; p.Q809R (c.2426A>G)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.50 Å; PDB: 6OP9
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.10 Å; PDB: 4RIX

RMSD: 1.24; TM score: 0.97473; Amino acid change: Q809R

• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.Q809R (c.2426A>G) in gene ERBB3 cause the sensitivity of PI3K pathway inhibitors + MEK inhibitors by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PI3K pathway inhibitors/MEK inhibitors
• Molecule Alteration: Missense mutation; p.Q809R (c.2426A>G)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.50 Å; PDB: 6OP9
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.10 Å; PDB: 4RIX

RMSD: 1.24; TM score: 0.97473; Amino acid change: Q809R

• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.Q809R (c.2426A>G) in gene ERBB3 cause the sensitivity of PI3K pathway inhibitors + MEK inhibitors by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PI3K pathway inhibitors/MEK inhibitors
• Molecule Alteration: Missense mutation; p.P262H (c.785C>A)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.P262H (c.785C>A) in gene ERBB3 cause the sensitivity of PI3K pathway inhibitors + MEK inhibitors by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PI3K pathway inhibitors/MEK inhibitors
• Molecule Alteration: Missense mutation; p.G284R (c.850G>A)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.G284R (c.850G>A) in gene ERBB3 cause the sensitivity of PI3K pathway inhibitors + MEK inhibitors by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PI3K pathway inhibitors/MEK inhibitors
• Molecule Alteration: Missense mutation; p.P262H (c.785C>A)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.P262H (c.785C>A) in gene ERBB3 cause the sensitivity of PI3K pathway inhibitors + MEK inhibitors by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PI3K pathway inhibitors/MEK inhibitors
• Molecule Alteration: Missense mutation; p.G284R (c.850G>A)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.G284R (c.850G>A) in gene ERBB3 cause the sensitivity of PI3K pathway inhibitors + MEK inhibitors by unusual activation of pro-survival pathway

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.51E-01; Fold-change: 1.01E-01; Z-score: 1.65E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.36E-03; Fold-change: 1.66E-01; Z-score: 3.95E-01

References

• Ref 1: MicroRNA-205 increases the sensitivity of docetaxel in breast cancer. Oncol Lett. 2016 Feb;11(2):1105-1109. doi: 10.3892/ol.2015.4030. Epub 2015 Dec 11.
• Ref 2: microRNA-205 regulates HER3 in human breast cancer. Cancer Res. 2009 Mar 15;69(6):2195-200. doi: 10.1158/0008-5472.CAN-08-2920. Epub 2009 Mar 10.
• Ref 3: Breast Cancer Anti-Estrogen Resistance 4 (BCAR4) Drives Proliferation of IPH-926 lobular Carcinoma Cells. PLoS One. 2015 Aug 28;10(8):e0136845. doi: 10.1371/journal.pone.0136845. eCollection 2015.
• Ref 4: YAP Regulates HER3 Signaling-Driven Adaptive Resistance to RET Inhibitors in RET-Aberrant Cancers. Clin Cancer Res. 2025 Mar 17;31(6):1127-1141.
• Ref 5: Oncogenic ERBB3 mutations in human cancersCancer Cell. 2013 May 13;23(5):603-17. doi: 10.1016/j.ccr.2013.04.012.