Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTDC8N2)

• DTT Name: Erbb3 tyrosine kinase receptor (Erbb-3)
• Synonyms: Tyrosine kinase-type cell surface receptor HER3; Receptor tyrosine-protein kinase erbB-3; Proto-oncogene-like protein c-ErbB-3; HER3; C-erbB3; C-erbB-3 protein
• Gene Name: ERBB3
• DTT Type: Clinical trial target; [1]
• Related Disease:
  Colorectal cancer [ICD-11: 2B91]
  Head and neck cancer [ICD-11: 2D42]
  Pancreatic cancer [ICD-11: 2C10]
  Psoriasis [ICD-11: EA90]
  Squamous cell carcinoma [ICD-11: 2B60-2D01]
  Breast cancer [ICD-11: 2C60-2C6Y]
  Malignant mesenchymal neoplasm [ICD-11: 2B5D-2B5Y]
  Lung cancer [ICD-11: 2C25]
  Metastatic lymph node neoplasm [ICD-11: 2D60]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• BioChemical Class: Kinase
• UniProt ID: ERBB3_HUMAN
• TTD ID: T86350
• EC Number: EC 2.7.10.1
• Sequence:
  MRANDALQVLGLLFSLARGSEVGNSQAVCPGTLNGLSVTGDAENQYQTLYKLYERCEVVM
  GNLEIVLTGHNADLSFLQWIREVTGYVLVAMNEFSTLPLPNLRVVRGTQVYDGKFAIFVM
  LNYNTNSSHALRQLRLTQLTEILSGGVYIEKNDKLCHMDTIDWRDIVRDRDAEIVVKDNG
  RSCPPCHEVCKGRCWGPGSEDCQTLTKTICAPQCNGHCFGPNPNQCCHDECAGGCSGPQD
  TDCFACRHFNDSGACVPRCPQPLVYNKLTFQLEPNPHTKYQYGGVCVASCPHNFVVDQTS
  CVRACPPDKMEVDKNGLKMCEPCGGLCPKACEGTGSGSRFQTVDSSNIDGFVNCTKILGN
  LDFLITGLNGDPWHKIPALDPEKLNVFRTVREITGYLNIQSWPPHMHNFSVFSNLTTIGG
  RSLYNRGFSLLIMKNLNVTSLGFRSLKEISAGRIYISANRQLCYHHSLNWTKVLRGPTEE
  RLDIKHNRPRRDCVAEGKVCDPLCSSGGCWGPGPGQCLSCRNYSRGGVCVTHCNFLNGEP
  REFAHEAECFSCHPECQPMEGTATCNGSGSDTCAQCAHFRDGPHCVSSCPHGVLGAKGPI
  YKYPDVQNECRPCHENCTQGCKGPELQDCLGQTLVLIGKTHLTMALTVIAGLVVIFMMLG
  GTFLYWRGRRIQNKRAMRRYLERGESIEPLDPSEKANKVLARIFKETELRKLKVLGSGVF
  GTVHKGVWIPEGESIKIPVCIKVIEDKSGRQSFQAVTDHMLAIGSLDHAHIVRLLGLCPG
  SSLQLVTQYLPLGSLLDHVRQHRGALGPQLLLNWGVQIAKGMYYLEEHGMVHRNLAARNV
  LLKSPSQVQVADFGVADLLPPDDKQLLYSEAKTPIKWMALESIHFGKYTHQSDVWSYGVT
  VWELMTFGAEPYAGLRLAEVPDLLEKGERLAQPQICTIDVYMVMVKCWMIDENIRPTFKE
  LANEFTRMARDPPRYLVIKRESGPGIAPGPEPHGLTNKKLEEVELEPELDLDLDLEAEED
  NLATTTLGSALSLPVGTLNRPRGSQSLLSPSSGYMPMNQGNLGESCQESAVSGSSERCPR
  PVSLHPMPRGCLASESSEGHVTGSEAELQEKVSMCRSRSRSRSPRPRGDSAYHSQRHSLL
  TPVTPLSPPGLEEEDVNGYVMPDTHLKGTPSSREGTLSSVGLSSVLGTEEEDEDEEYEYM
  NRRRRHSPPHPPRPSSLEELGYEYMDVGSDLSASLGSTQSCPLHPVPIMPTAGTTPDEDY
  EYMNRQRDGGGPGGDYAAMGACPASEQGYEEMRAFQGPGHQAPHVHYARLKTLRSLEATD
  SAFDNPDYWHSRLFPKANAQRT
• Function: 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. Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins.
• KEGG Pathway:
  ErbB signaling pathway (hsa04012)
  Calcium signaling pathway (hsa04020)
  Endocytosis (hsa04144)
  Proteoglycans in cancer (hsa05205)
  MicroRNAs in cancer (hsa05206)
• Reactome Pathway:
  Signaling by ERBB4 (R-HSA-1236394)
  SHC1 events in ERBB2 signaling (R-HSA-1250196)
  PIP3 activates AKT signaling (R-HSA-1257604)
  GRB7 events in ERBB2 signaling (R-HSA-1306955)
  Downregulation of ERBB2 (R-HSA-1358803)
  PI3K events in ERBB2 signaling (R-HSA-1963642)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  RAF/MAP kinase cascade (R-HSA-5673001)
  ERBB2 Regulates Cell Motility (R-HSA-6785631)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  ERBB2 Activates PTK6 Signaling (R-HSA-8847993)
  Downregulation of ERBB2 signaling (R-HSA-8863795)
  Signaling by ERBB2 KD Mutants (R-HSA-9664565)
  Signaling by ERBB2 TMD/JMD mutants (R-HSA-9665686)
  Signaling by ERBB2 (R-HSA-1227986)

Molecular Interaction Atlas (MIA) of This DTT

21 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CDX-3379	DM5GKYD	Squamous cell carcinoma	2B60-2D01	Phase 2	[2]
Elisidepsin	DMB38KH	Psoriasis vulgaris	EA90	Phase 2	[1]
MEHD-7945A	DMHOF7T	Colorectal cancer	2B91.Z	Phase 2	[3], [4]
MM-121	DMDJRU1	Breast cancer	2C60-2C65	Phase 2	[5]
MM-141	DM2RJ4D	Pancreatic cancer	2C10	Phase 2	[6]
Seribantumab	DMYT470	Colorectal cancer	2B91.Z	Phase 2	[2]
AMG888/U3-1287	DMEF4L5	Non-small-cell lung cancer	2C25.Y	Phase 1/2	[7]
LJM716	DMGTB5N	Breast cancer	2C60-2C65	Phase 1/2	[8]
Sym013	DMZM6I2	Epithelial ovarian cancer	2B5D	Phase 1/2	[9]
Zenocutuzomab	DMMQGPE	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[10]
Anti-HER3/EGFR DAF	DMDMNJ6	Metastatic epithelial tumour	2D60	Phase 1	[3]
AV-203	DMZLCTD	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
Drug 2849330	DMM57CS	Solid tumour/cancer	2A00-2F9Z	Phase 1	[12], [13]
GSK2849330	DM6KE4G	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]
KTN3379	DM8FQPX	Solid tumour/cancer	2A00-2F9Z	Phase 1	[14]
MM-151	DMXQHZC	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]
Patritumab	DMFSMCB	Non-small-cell lung cancer	2C25.Y	Phase 1	[15]
Recombinant human Erbb3 fragment therapeutic tumor vaccine	DMK9Y71	Solid tumour/cancer	2A00-2F9Z	Phase 1	[16]
REGN1400	DME3VU8	Solid tumour/cancer	2A00-2F9Z	Phase 1	[17]
RG7116	DM6XVCO	Solid tumour/cancer	2A00-2F9Z	Phase 1	[18]
SI-B001	DMDSFEB	Metastatic epithelial tumour	2D60	Phase 1	[19]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MP-RM-1	DMFKG7C	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
Soluble ErbB3 theragnostics	DMJXN1G	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
SYM-011	DMKIDRY	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Lung cancer	2C82	Lung tissue	7.21E-05	-0.32	-0.62
Breast cancer	2C82	Breast tissue	3.51E-01	0.1	0.17
Psoriasis	EA90	Skin	6.18E-05	-0.33	-0.75

References

• [1] Molecular pharmacodynamics of PM02734 (elisidepsin) as single agent and in combination with erlotinib; synergistic activity in human non-small cell lung cancer cell lines and xenograft models. Eur J Cancer. 2009 Jul;45(10):1855-64.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Company report (Biooncology)
• [4] Bispecific antibodies rise again. Nat Rev Drug Discov. 2014 Nov;13(11):799-801.
• [5] Company report (Merrimack)
• [6] MM-141, an IGF-IR- and ErbB3-directed bispecific antibody, overcomes network adaptations that limit activity of IGF-IR inhibitors. Mol Cancer Ther. 2014 Feb;13(2):410-25.
• [7] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1798).
• [8] An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Res. 2013 Oct 1;73(19):6024-35.
• [9] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [10] Clinical pipeline report, company report or official report of Merus.
• [11] Neuregulin 1 expression is a predictive biomarker for response to AV-203, an ERBB3 inhibitory antibody, in human tumor models. Clin Cancer Res. 2015 Mar 1;21(5):1106-14.
• [12] National Cancer Institute Drug Dictionary (drug id 754219).
• [13] Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery. Nucleic Acids Res. 2012 Jan;40(Database issue):D1128-36.
• [14] A critical role for HER3 in HER2-amplified and non-amplified breast cancers: function of a kinase-dead RTK. Am J Transl Res. 2015; 7(4): 733-750.
• [15] Phase 1 and dose-finding study of patritumab (U3-1287), a human monoclonal antibody targeting HER3, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2014 Mar;73(3):511-6.
• [16] Clinical pipeline report, company report or official report of Zensun.
• [17] J Clin Oncol 32:5s, 2014 (suppl; abstr 2516).
• [18] RG7116, a therapeutic antibody that binds the inactive HER3 receptor and is optimized for immune effector activation. Cancer Res. 2013 Aug 15;73(16):5183-94.
• [19] Clinical pipeline report, company report or official report of SystImmune.