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HER3 is a cousin of HER2 that cancers use as an escape route when HER2 or EGFR are blocked.
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.
In plain words · HER3 is a cousin of HER2 that cancers use as an escape route when HER2 or EGFR are blocked.
Backbone ribbon from PDB 1S78. RCSB PDB 1S78. The ribbon widens where the chain is folded into a regular pattern and narrows where it is a loose loop.
HER3 is a cousin of HER2 that cancers use as an escape route when HER2 or EGFR are blocked.
Neuregulin (NRG1) ligand; NRG1 fusions are rare drivers targeted by zenocutuzumab. Broadly expressed across breast, lung, and colorectal cancers.
8 products aim at HER3: antibodies, antibody-drug conjugates and bispecific antibodies. Because it sits on the outside of the cell, it can be reached from the bloodstream: antibodies flag the cell, ADCs deliver a toxin, radioligands deliver radiation, and CAR-T or bispecifics bring a T cell.
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.)
Sources: Human Protein Atlas ERBB3 tissue; Human Protein Atlas ERBB3 pathology; Open Targets ENSG00000065361 associations
First described 1989. 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". Source.
What a pathology or genomic report can say about this target, each with the thresholds approvals use.
Neuregulin (NRG1) ligand; NRG1 fusions are rare drivers targeted by zenocutuzumab. Broadly expressed across breast, lung, and colorectal cancers.
RNA: low tissue specificity, detected in many normal tissues. Blood: lineage enriched (granulocytes 1 nTPM).
Medium: Adipose tissue, Bone marrow, Breast, Endometrium, Fallopian tube, Hippocampus, Liver, Lung.
Medium only: lymphoma, thyroid cancer.
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Non-small-cell lung cancer | 80-90% | IHC, any expression | EGFR-mutant NSCLC in HERTHENA-Lung01 | Wikipedia |
| Triple-negative breast cancer | 50-70% | IHC, any expression | Wikipedia | |
| HR-positive / HER2-negative breast cancer | 50-70% | IHC, any expression | Wikipedia | |
| Gallbladder cancer | 7-12% | Mutation (amplification rarer) | 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. | doi.org |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
ENV-501 is an experimental antibody-drug conjugate from Hummingbird Bioscience in phase 2 trials for melanoma, non-small-cell lung cancer and HR-positive / HER2-negative breast cancer, aimed at HER3.
HMBD-001 is an experimental monoclonal antibody from Hummingbird Bioscience in phase 2 trials for non-small-cell lung cancer, head and neck squamous cell carcinoma and oesophageal cancer, aimed at HER3 and EGFR.
Izalontamab brengitecan is the first bispecific ADC to succeed in a phase 3 trial, hitting two growth receptors at once in triple-negative breast cancer.
A HER3-directed ADC with Enhertu's payload, active in lung and all subtypes of breast cancer, but with a bumpy regulatory road.
A second HER2 antibody that binds a different spot from trastuzumab, blocking HER2 from pairing with HER3; together they extended survival by 16 months in CLEOPATRA.
SYS6023 is an experimental antibody-drug conjugate from CSPC Megalith Biopharmaceutical in phase 2 trials for HR-positive / HER2-negative breast cancer, aimed at HER3.
YL202 is an experimental antibody-drug conjugate (ADC) from MediLink Therapeutics (Suzhou) in phase 3 trials for non-small-cell lung cancer, HR-positive / HER2-negative breast cancer and colorectal cancer, aimed at HER3.
Zenocutuzumab is the first drug for cancers driven by NRG1 gene fusions, working by blocking HER3 from receiving its growth signal.
Every KRAS wild-type pancreatic cancer should be tested for NRG1 fusions because a specific, approved antibody now exists; zenocutuzumab is the first targeted drug approved for a pancreatic cancer driver.
Together with the German MASTER report, this paper is why guidelines recommend comprehensive profiling with fusion detection in KRAS wild-type pancreatic cancer.
Regional biology is real but partial: exposures and age differ, some genes differ, and SMAD4 loss emerges as the shared bad-prognosis marker. It is the paper behind the MSK 2018 gallbladder study on cBioPortal (gbc_msk_2018).
KRAS wild-type status should trigger fusion testing, ideally by RNA sequencing, because NRG1 fusions can be targeted by HER-family inhibitors and now by zenocutuzumab.
This paper put HER-family signalling at the centre of gallbladder cancer biology a decade before HER2-directed drugs were approved for it, and it is why ERBB2 and ERBB3 sit near the top of every later panel study.
This review is the conceptual basis for trastuzumab, pertuzumab, HER2 antibody-drug conjugates and EGFR inhibitors, and for the HER3-mediated resistance that later drugs try to overcome.
Query for this target: (TITLE:"HER3" OR ABSTRACT:"HER3" OR TITLE:"ERBB3" OR ABSTRACT:"ERBB3") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about HER3, not a curated reading list.
Shares Re-map the tumour's surface proteins before choosing the next antibody drug, Antibody-drug conjugate (ADC), Triple-negative breast cancer (TNBC), Non-small-cell lung cancer and the tag adc-target.
Shares Re-map the tumour's surface proteins before choosing the next antibody drug, Bispecific ADC, Antibody-drug conjugate (ADC) and the tag adc-target.
Shares Bispecific ADC, Antibody-drug conjugate (ADC), Triple-negative breast cancer (TNBC) and the tag adc-target.
Shares Antibody-drug conjugate (ADC), Triple-negative breast cancer (TNBC) and the tag adc-target.
Shares Antibody-drug conjugate (ADC), Pancreatic ductal adenocarcinoma and the tag adc-target.
Shares Antibody-drug conjugate (ADC) and the tag adc-target.
Shares Antibody-drug conjugate (ADC) and the tag adc-target.
Shares Antibody-drug conjugate (ADC) and the tag adc-target.