ERBB4 erb-b2 receptor tyrosine kinase 4
ENSG00000178568 · protein coding · Open Targets profile
Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context- specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM- A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis. {ECO:0000269|PubMed:10348342, ECO:0000269|PubMed:10353604, ECO:0000269|PubMed:10358079, ECO:0000269|PubMed:10722704, ECO:0000269|PubMed:10867024, ECO:0000269|PubMed:11178955, ECO:0000269|PubMed:11390655, ECO:0000269|PubMed:12807903, ECO:0000269|PubMed:15534001, ECO:0000269|PubMed:15746097, ECO:0000269|PubMed:16251361, ECO:0000269|PubMed:16778220, ECO:0000269|PubMed:16837552, ECO:0000269|PubMed:17486069, ECO:0000269|PubMed:17638867, ECO:0000269|PubMed:19098003, ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:8383326, ECO:0000269|PubMed:8617750, ECO:0000269|PubMed:9135143, ECO:0000269|PubMed:9168115, ECO:0000269|PubMed:9334263}.
Each band is a group of drugs. It runs from the kind of drug on the left to the furthest stage that drug has reached in any disease on the right. Thicker bands mean more drugs.
Approved bands are highlighted. Withdrawn means the drug was pulled from the market or from development. A combined phase counts as the later one (Phase 1/2 is shown as Phase 2). Hover a band for the drug names. Source: Open Targets Platform, fetched live.
Each row is a cancer, strongest overall evidence first. The two dots show how strong the inherited (germline) and tumour-mutation (somatic) evidence is; the line between them is the gap.
Scores run from 0 (no evidence) to 1 (strongest). A missing dot at 0 means Open Targets holds no evidence of that kind. Source: Open Targets Platform, fetched live.
Tractability
- Small molecule
- Approved Drug, Structure with Ligand, High-Quality Ligand, High-Quality Pocket, Druggable Family
- Antibody
- UniProt loc high conf, GO CC high conf, UniProt SigP or TMHMM
- PROTAC
- UniProt Ubiquitination, Database Ubiquitination, Half-life Data, Small Molecule Binder
- Other modalities
- Phase 1 Clinical
gnomAD loss of function constraint: o/e 0.265859991312027 (upper bound 0.34387001395225525). Low values mean loss of function is poorly tolerated, a safety flag for inhibition.
Who runs trials of these drugs
Principal investigators and study chairs on 136 registry trials, updated in the last three years, of the most advanced drugs against ERBB4 (afatinib, neratinib, dacomitinib, vandetanib, poziotinib, canertinib, dacomitinib anhydrous, tarloxotinib, BMS-690514, AC-480), ranked by Phase 2+ trials. Live from ClinicalTrials.gov.
- Xingchen PengWest China Hospital · 3 of 5 trials Phase 2+Ph1NCT06741982 · A Clinical Study on Neoadjuvant Treatment of Resectable Head and Neck Squamous Carcinoma With Immune-targeted Therapy and Lysogenic HSV Virusbrief
- Oscar ArrietaInstituto Nacional de Cancerologia de Mexico · 2 of 2 trials Phase 2+
- Rachel LaymanM.D. Anderson Cancer Center · 2 of 2 trials Phase 2+
- Andrew PoklepovicMassey Cancer Center · 1 of 2 trials Phase 2+
- Jamuna ThimmarayappaArriVent BioPharm · 1 of 2 trials Phase 2+
- Aarti BhatiaYale University · 1 of 1 trials Phase 2+
- AJ GelderblomLeiden University Medical Center · 1 of 1 trials Phase 2+
- Ajay DhakalUniversity of Rochester · 1 of 1 trials Phase 2+
- Alessandro SantinYale University · 1 of 1 trials Phase 2+
- Asona LuiUC San Diego · 1 of 1 trials Phase 2+
- Boon Cher GohNational University of Singapore · 1 of 1 trials Phase 2+
- Bristol-Myers SquibbBristol-Myers Squibb · 1 of 1 trials Phase 2+
- Chau DangMemorial Sloan Kettering Cancer Center · 1 of 1 trials Phase 2+
- Chief Scientific OfficerPuma Biotechnology, Inc. · 1 of 1 trials Phase 2+
- Christoph HeiningNational Center of Tumor Diseases (NCT) Dresden · 1 of 1 trials Phase 2+
Registry trials of afatinib, neratinib, dacomitinib, vandetanib, poziotinib, canertinib, dacomitinib anhydrous, tarloxotinib, BMS-690514, AC-480 updated in the last three years, counted by the country group of their listed sites. A trial with sites in several groups counts in each; 100 of 129 have all sites in one country.
Site counts are not patients per country, and trials registered only outside ClinicalTrials.gov are not covered. Where sites are is a fact about the record, not a judgement of its quality. Europe is the EU and EEA, the UK and Switzerland. 7 trials list no sites and are left out. Source: ClinicalTrials.gov, fetched live.
92 trials of drugs against ERBB4 were stopped early; 8 give no reason
Terminated, withdrawn and suspended interventional trials of afatinib, neratinib, dacomitinib, vandetanib, poziotinib, canertinib, dacomitinib anhydrous, tarloxotinib, BMS-690514, AC-480, KBP5209, JNJ-26483327, newest update first, live from ClinicalTrials.gov. Each reason is quoted exactly as the registry gives it; we do not sort reasons into safety, efficacy or business. Dates are the last registry update. Showing the 25 most recent of 92.
- suspended · 2026-10-28 · Spectrum Pharmaceuticals, Inc · Poziotinib“The study has not enrolled any patients. The study design is under discussion and will likely be redesigned in consultation with the FDA.”
- suspended · 2026-10-21 · Virginia Commonwealth University · Neratinib“Pending amendment approval”
- withdrawn · 2026-10-16 · West China Hospital · Afatinib“The study was withdrawn prior to participant enrollment due to administrative and protocol optimization considerations.”
- terminated · 2026-07-28 · Spectrum Pharmaceuticals, Inc · Poziotinib“Business reasons, not related to safety.”
- terminated · 2026-07-22 · M.D. Anderson Cancer Center · Neratinib“<75% participation”
- terminated · 2026-06-12 · Spectrum Pharmaceuticals, Inc · Poziotinib“Strategic business decision (unrelated to safety)”
- terminated · 2026-06-03 · Petrov, Andrey · Afatinib Dimaleat, inhalation of afatinib dimaleate“adjustment of the study design taking into account the receipt of primary data”
- terminated · 2026-04-27 · Partner Therapeutics, Inc. · Afatinib Oral Tablet“Merus terminated the study early due to changes in organizational priorities.”
- terminated · 2026-02-20 · M.D. Anderson Cancer Center · Poziotinib“<75% participation”
- terminated · 2026-02-12 · M.D. Anderson Cancer Center · Neratinib“<75% accrued”
- terminated · 2026-01-22 · Dana-Farber Cancer Institute · Neratinib“Slow accrual”
- terminated · 2025-12-16 · Medical University of South Carolina · Sotorasib and Tarloxotinib“Study drug was discontinued by manufacturer for business reasons.”
- withdrawn · 2025-11-19 · West China Hospital · Afatinib“The study was withdrawn prior to participant enrollment due to administrative and protocol optimization considerations.”
- terminated · 2025-06-11 · M.D. Anderson Cancer Center · Neratinib“Sponsor Withdrew Support”
- terminated · 2025-04-25 · University of Chicago · afatinib dimaleate“Unable to meet accrual goal after several years”
- terminated · 2025-02-11 · Boehringer Ingelheim · BIBW 2992 (Afatinib)No reason given
- terminated · 2024-06-25 · Spectrum Pharmaceuticals, Inc · Poziotinib Once Daily Dosing, Poziotinib Twice Daily Dosing, Poziotinib Once Daily Dosing or Twice Daily Dosing as determined in Phase 1“Business decision, not related to safety.”
- terminated · 2024-03-13 · Spectrum Pharmaceuticals, Inc · Poziotinib Hydrochloride“Strategic business decision (unrelated to safety)”
- terminated · 2024-03-12 · Puma Biotechnology, Inc. · Neratinib“The study was terminated to align with the sponsor's current development plans for neratinib. The decision was not based on any new efficacy or safety data for neratinib.”
- terminated · 2024-03-04 · OHSU Knight Cancer Institute · Afatinib, Dacomitinib, Neratinib“Low accrual”
- terminated · 2024-01-31 · Cambridge University Hospitals NHS Foundation Trust · Afatinib“Slow recruitment”
- withdrawn · 2024-01-05 · Hoffmann-La Roche · Vandetanib“Due to several logistical challenges during start-up which could not be overcome study was withdrawn.”
- withdrawn · 2023-09-13 · M.D. Anderson Cancer Center · Poziotinib Hydrochloride, 1429757-68-5, HM781-36B, NOV-1201 Hydrochloride, NOV120101 Hydrochloride, Poziotinib HCl, POZIOTINIB HYDROCHLORIDE“Study closed due to funding, 0 patient accrual.”
- withdrawn · 2023-08-01 · Massachusetts General Hospital · NERATINIB“Team decision”
- withdrawn · 2023-07-11 · Beth Israel Deaconess Medical Center · Neratinib“Withdrawal of funding”
Paediatric incentives and obligations for ERBB4's drugs
For afatinib, neratinib, dacomitinib, vandetanib, poziotinib, canertinib, dacomitinib anhydrous, tarloxotinib, BMS-690514, AC-480, KBP5209, JNJ-26483327: what EMA and FDA publish about paediatric plans, orphan status and pediatric approvals, and how many registered studies take children. Each line is a yes, no or not published fact from the record linked under it; none of it is a forecast.
- FDA pediatric target list: no · ERBB4 is not on the listRule: Target is on FDA's Pediatric Molecular Target List (relevant targets). Source: FDA Pediatric Molecular Target List (Listed as February 2026 on the FDA Pediatric Oncology page; the file served is 9.7.22_the_relevant_molecular_target_list.xlsx, whose Summary of Changes sheet is headed 'SEPTEMBER 2022 UPDATE' (footnote date 2022-09-01)), 2026-11-11
- EU paediatric investigation plan: yes · EMEA-001596-PIP02-17-M02 (afatinib, Treatment of all conditions included in the category of malignant neoplasms (excluding central nervous system, haematopoietic and lymphoid tissue neoplasms);Treatment of malignant neoplasms of the central nervous system): PM: decision on the application for modification of an agreed PIP, 13 May 2020; compliance positive 23 Apr 2021; EMEA-002783-PIP01-20 (neratinib, Treatment of breast cancer): W: decision granting a waiver in all age groups for all conditions or indications, 15 Jul 2020; EMEA-000052-PIP01-07-M03 (vandetanib, Treatment of medullary thyroid carcinoma): PM: decision on the application for modification of an agreed PIP, 30 Nov 2013; compliance positive 20 Jun 2014Rule: An EMA PIP decision (agreement, modification or waiver) lists the drug as its active substance, exact name. Source: EMA data download (dated snapshot), 2026-11-11
- EU orphan designation: yes · EU/3/24/2929 positive 28 Jun 2024: Treatment of complex regional pain syndrome; EU/3/18/2110 positive 14 Dec 2018: Treatment of Fanconi anaemia; EU/3/05/344 withdrawn 24 Jan 2006: Treatment of medullary thyroid carcinomaRule: An EU orphan designation lists the drug as its active substance (exact name) or belongs to a medicine that does; withdrawn and expired designations are listed with their status. Source: EMA data download (dated snapshot), 2026-11-11
- Authorised in the EU: yes · Vizimpro: authorised since 2 Apr 2019; Caprelsa: authorised since 16 Feb 2012; Giotrif: authorised since 25 Sept 2013; Nerlynx: authorised since 31 Aug 2018; +1 moreRule: An EMA medicine record lists the drug as its active substance or INN, exact name; national-only authorisations are not in this file. Source: EMA data download (dated snapshot), 2026-11-11
- FDA orphan designation: not published · FDA's orphan designation database turns away automated requests, so this app does not read it; search it by hand at the linkRule: Would be: an FDA orphan designation names the drug. Source: FDA orphan designations search
- FDA pediatric oncology approval: no · FDA's table lists no pediatric approval of afatinib, neratinib, dacomitinib, vandetanib, poziotinib, canertinib, dacomitinib anhydrous, tarloxotinib, bms-690514, ac-480, kbp5209, jnj-26483327Rule: FDA's Pediatric Oncology Drug Approvals table names the drug. Source: FDA Pediatric Oncology Drug Approvals (content current as of 2026-03-03), 2026-11-11
- Registered studies open to children: yes · 21 interventional studies of afatinib, neratinib, dacomitinib, vandetanib, poziotinib, canertinib, dacomitinib anhydrous, tarloxotinib, bms-690514, ac-480, kbp5209, jnj-26483327 include patients under 18; 5 are recruiting, not yet recruiting or activeRule: The registry's age group includes Child (birth to 17 years), which also counts studies that set no minimum age. Source: ClinicalTrials.gov search, 2026-11-11
Rare pediatric disease voucher. FDA, content current as of 29 Apr 2026: “As of February 3, 2026, enactment of the Consolidated Appropriations Act, 2026, the rare pediatric disease PRV program will sunset after September 30, 2029. FDA may not award any PRVs under this program after September 30, 2029.” Voucher sale prices are not shown here; they appear only as company-reported news. FDA: Rare Pediatric Disease Designation and Priority Review Voucher Programs
All 15 drugs and clinical candidates as a table
Each drug, stage and indication links to its Open Targets record, where the trials and approvals behind it are listed. Salt forms (for example a mesylate) are listed as Open Targets records them, as separate entries.