{"entity":{"id":"her3","kind":"target","name":"HER3","aka":[],"tldr":"HER3 is a cousin of HER2 that cancers use as an escape route when HER2 or EGFR are blocked.","summary":"HER3 (ERBB3) has weak kinase activity but is the preferred dimerisation partner of HER2 and a frequent driver of resistance to EGFR and HER2 inhibitors, which is why it matters more as an escape route than as a driver in its own right. Its ligand is neuregulin (NRG1), and rare NRG1 fusions are drivers targeted by zenocutuzumab. HER3 is broadly expressed across breast, lung, and colorectal cancers, including 80-90% of EGFR-mutant NSCLC and 50-70% of breast cancers by IHC. Patritumab deruxtecan (HER3-DXd) and the EGFR×HER3 bispecific ADC izalontamab brengitecan make it a delivery target rather than a signalling target, with HERTHENA-Lung01 testing HER3-DXd in EGFR-mutant NSCLC. The open question is whether expression level predicts benefit. The simple version is a HER2 cousin that cancers switch to when HER2 or EGFR is blocked.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/ERBB3","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/ERBB3"}],"tags":["adc-target","resistance"],"related":["nrg1-fusion","her3-expression"],"cancers":["tnbc","nsclc","breast-hr-positive","gallbladder"],"sections":[],"technologies":[],"targets":[],"drugs":["yl202","hmbd-001","env-501","sys6023"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-li-gallbladder-exome-erbb-nat-genet-2014","paper-narayan-gallbladder-regional-mutations-cancer-2019"],"journals":[],"dependsOn":[],"notes":["Gallbladder cancer: ERBB3 was a significantly mutated gene (11.8% of 57) in the first exome study, and ErbB pathway mutation as a whole marked a worse outcome (Li 2014)."],"symbol":"ERBB3","role":[],"sources":[],"specificity":"tumour-associated","distribution":"few-types","specificityNote":"Tumour-associated overexpression: 5 cell-killing or cell-finding medicines (YL202, ENV-501, SYS6023 and more) aim at the antigen, which HPA finds stained high in 27 normal tissues; the medicine relies on the tumour carrying more of it than the normal tissue it shares it with. HPA ERBB3: RNA low tissue specificity; blood lineage lineage enriched (granulocytes 1 nTPM); high antibody staining in 27 normal tissues; highest cancer staining stomach cancer (7 of 9 high). Distribution: 3 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Breast cancer (all types), Lung cancer (all types), Biliary tract cancer (all types)); Open Targets associates it with 5 specific cancer types at or above 0.5 (urinary bladder cancer, urinary bladder carcinoma, non-small cell lung carcinoma, medullary thyroid gland carcinoma, colorectal adenocarcinoma). (Rule 5 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"Human Protein Atlas ERBB3 tissue","url":"https://www.proteinatlas.org/ENSG00000065361-ERBB3/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Human Protein Atlas ERBB3 pathology","url":"https://www.proteinatlas.org/ENSG00000065361-ERBB3/pathology","note":"patients per staining level per cancer type (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000065361 associations","url":"https://platform.opentargets.org/target/ENSG00000065361/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:3431","ensembl":"ENSG00000065361","uniprot":"P21860","entrez":"2065","firstDescribed":1989,"firstDescribedBasis":"sequence","firstDescribedNote":"Earliest sequence paper UniProt cites for the protein: Kraus M.H. et al, Proc. Natl. Acad. Sci. U.S.A, 1989, \"Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/2687875/","biology":"Neuregulin (NRG1) ligand; NRG1 fusions are rare drivers targeted by zenocutuzumab. Broadly expressed across breast, lung, and colorectal cancers.","whereFound":["Breast cancer (all subtypes)","EGFR-mutant NSCLC","Colorectal","NRG1-fusion tumours","Gallbladder cancer: mutation (amplification rarer) 7-12%"],"targetClass":"surface-antigen","prevalence":[{"cancerId":"tnbc","pct":"50-70","measure":"IHC, any expression","source":"https://en.wikipedia.org/wiki/ERBB3"},{"cancerId":"nsclc","pct":"80-90","measure":"IHC, any expression","source":"https://en.wikipedia.org/wiki/ERBB3","note":"EGFR-mutant NSCLC in HERTHENA-Lung01"},{"cancerId":"breast-hr-positive","pct":"50-70","measure":"IHC, any expression","source":"https://en.wikipedia.org/wiki/ERBB3"},{"cancerId":"gallbladder","pct":"7-12","measure":"Mutation (amplification rarer)","source":"https://doi.org/10.1038/ng.3030","note":"11.8% of 57 (Li 2014, a significantly mutated gene); mutation in 16 of 244 samples, 6.6%, and amplification in 12 of 244, 4.9%, in cBioPortal gbc_mskcc_2022; absent from the 21 Chilean tumours in Narayan 2019."}]},"route":"/targets/her3/","neighbours":{"biomarker":[{"id":"her3-expression","kind":"biomarker","name":"HER3 expression","route":"/biomarkers/her3-expression/"},{"id":"nrg1-fusion","kind":"biomarker","name":"NRG1 gene fusion","route":"/biomarkers/nrg1-fusion/"}],"cancer":[{"id":"cholangiocarcinoma","kind":"cancer","name":"Biliary tract cancer (cholangiocarcinoma)","route":"/cancers/cholangiocarcinoma/"},{"id":"egfr-mutant-nsclc","kind":"cancer","name":"EGFR-mutated non-small-cell lung cancer","route":"/cancers/egfr-mutant-nsclc/"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","route":"/cancers/gallbladder/"},{"id":"breast-her2-positive","kind":"cancer","name":"HER2-positive breast cancer","route":"/cancers/breast-her2-positive/"},{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"kras-wild-type-pdac","kind":"cancer","name":"KRAS wild-type pancreatic ductal adenocarcinoma","route":"/cancers/kras-wild-type-pdac/"},{"id":"metastatic-pdac","kind":"cancer","name":"Metastatic pancreatic ductal adenocarcinoma","route":"/cancers/metastatic-pdac/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"esophageal","kind":"cancer","name":"Oesophageal cancer","route":"/cancers/esophageal/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"drug":[{"id":"env-501","kind":"drug","name":"ENV-501","route":"/drugs/env-501/"},{"id":"hmbd-001","kind":"drug","name":"HMBD-001","route":"/drugs/hmbd-001/"},{"id":"izalontamab-brengitecan","kind":"drug","name":"Izalontamab brengitecan","route":"/drugs/izalontamab-brengitecan/"},{"id":"patritumab-deruxtecan","kind":"drug","name":"Patritumab deruxtecan","route":"/drugs/patritumab-deruxtecan/"},{"id":"pertuzumab","kind":"drug","name":"Pertuzumab","route":"/drugs/pertuzumab/"},{"id":"sys6023","kind":"drug","name":"SYS6023","route":"/drugs/sys6023/"},{"id":"yl202","kind":"drug","name":"YL202","route":"/drugs/yl202/"},{"id":"zenocutuzumab","kind":"drug","name":"Zenocutuzumab","route":"/drugs/zenocutuzumab/"}],"paper":[{"id":"paper-enrgy-zenocutuzumab-nrg1-fusion-positive-cancer-nejm-2025","kind":"paper","name":"eNRGy: efficacy of zenocutuzumab in NRG1 fusion-positive cancer","route":"/key-papers/paper-enrgy-zenocutuzumab-nrg1-fusion-positive-cancer-nejm-2025/"},{"id":"paper-heining-nrg1-fusions-kras-wild-type-pancreatic-cancer-discov-2018","kind":"paper","name":"Heining 2018: NRG1 fusions in KRAS wild-type pancreatic cancer","route":"/key-papers/paper-heining-nrg1-fusions-kras-wild-type-pancreatic-cancer-discov-2018/"},{"id":"paper-jones-nrg1-fusions-recurrent-actionable-kras-wild-type-pdac-ccr-2019","kind":"paper","name":"Jones 2019: NRG1 gene fusions are recurrent, clinically actionable rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma","route":"/key-papers/paper-jones-nrg1-fusions-recurrent-actionable-kras-wild-type-pdac-ccr-2019/"},{"id":"paper-narayan-gallbladder-regional-mutations-cancer-2019","kind":"paper","name":"Regional differences in gallbladder cancer pathogenesis: insights from a multi-institutional comparison of tumor mutations","route":"/key-papers/paper-narayan-gallbladder-regional-mutations-cancer-2019/"},{"id":"paper-li-gallbladder-exome-erbb-nat-genet-2014","kind":"paper","name":"Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway","route":"/key-papers/paper-li-gallbladder-exome-erbb-nat-genet-2014/"},{"id":"paper-yarden-sliwkowski-erbb-network-nrmcb-2001","kind":"paper","name":"Yarden and Sliwkowski 2001: untangling the ErbB signalling network","route":"/key-papers/paper-yarden-sliwkowski-erbb-network-nrmcb-2001/"}],"trial":[{"id":"nct02912949","kind":"trial","name":"A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion (eNRGy)","route":"/trials/nct02912949/"},{"id":"herthena-lung02","kind":"trial","name":"HERTHENA-Lung02","route":"/trials/herthena-lung02/"},{"id":"panku-esophagus01","kind":"trial","name":"PANKU-Esophagus01 (BL-B01D1-305)","route":"/trials/panku-esophagus01/"}],"term":[{"id":"dual-her2-blockade","kind":"term","name":"Dual HER2 blockade","route":"/terms/dual-her2-blockade/"}],"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"bispecific-adc","kind":"technology","name":"Bispecific ADC","route":"/technologies/bispecific-adc/"}],"person":[{"id":"helena-yu","kind":"person","name":"Helena A. Yu","route":"/people/helena-yu/"}],"idea":[{"id":"idea-bio1-stromal-resistance-blockade","kind":"idea","name":"Block the survival signals the tumour's neighbours provide","route":"/ideas/idea-bio1-stromal-resistance-blockade/"},{"id":"idea-bio1-antigen-mapping-at-progression","kind":"idea","name":"Re-map the tumour's surface proteins before choosing the next antibody drug","route":"/ideas/idea-bio1-antigen-mapping-at-progression/"},{"id":"idea-bio2-transferrin-shuttle-adc","kind":"idea","name":"Use the brain's own transport door to carry antibody drugs across","route":"/ideas/idea-bio2-transferrin-shuttle-adc/"}],"pathway":[{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}],"company":[{"id":"pathos-ai","kind":"company","name":"Pathos AI","route":"/companies/pathos-ai/"}]}}