NOTCH3 as a Radioligand Therapy Target
NOTCH3, notch receptor 3, is a cell-surface protein (membrane receptor). In Human Protein Atlas immunohistochemistry, NOTCH3 staining is highest in neuroendocrine tumors (100% of samples positive), colorectal cancer (100% of samples positive) and thyroid cancer (100% of samples positive). Published literature reports that NOTCH3 internalizes after ligand binding, which helps retain a radionuclide inside tumor cells. Clinical status: Clinical-stage (up to phase 2, any modality).
Is NOTCH3 a good radioligand therapy target?
Scored against the six criteria that decide whether a protein can become a radioligand therapy:
- ✅ Cell-surface accessibility: Localized to the cell surface, so a radioligand can reach it from circulation.
- ✅ Tumor expression: High IHC staining in neuroendocrine tumors, 100% of samples positive.
- ✅ Internalization: Reported to internalize, which favors radionuclide retention.
- ✅ Clinical precedent: Clinical-stage (up to phase 2, any modality)
- ❔ Shedding: Not yet assessed.
- ❔ Normal-tissue dosimetry: Check kidney, liver, bone marrow and salivary expression in the Human Protein Atlas tissue atlas.
NOTCH3 expression in cancer
Protein expression of NOTCH3 across 20 cancer types from Human Protein Atlas immunohistochemistry. The score is a weighted staining intensity from 0 to 1; "% positive" is the share of patient samples with detectable staining.
| Cancer type | IHC score | Level | % positive |
|---|---|---|---|
| Neuroendocrine Tumors | 0.75 | High | 100% |
| Colorectal Cancer | 0.69 | High | 100% |
| Thyroid Cancer | 0.67 | High | 100% |
| Endometrial Cancer | 0.64 | High | 91% |
| Breast Cancer | 0.61 | High | 83% |
| Bladder Cancer | 0.56 | High | 100% |
| Skin Cancer | 0.53 | High | 83% |
| Glioma | 0.52 | High | 82% |
| Head and Neck Cancer | 0.50 | Medium | 100% |
| Cervical Cancer | 0.50 | Medium | 92% |
| Lymphoma | 0.50 | Medium | 80% |
| Testicular Cancer | 0.47 | Medium | 83% |
| Gastric Cancer | 0.44 | Medium | 92% |
| Liver Cancer | 0.42 | Medium | 82% |
| Ovarian Cancer | 0.42 | Medium | 83% |
| Melanoma | 0.39 | Medium | 73% |
| Prostate Cancer | 0.36 | Medium | 75% |
| Pancreatic Cancer | 0.36 | Medium | 67% |
| Kidney Cancer | 0.30 | Medium | 55% |
| Lung Cancer | 0.22 | Medium | 50% |
Is NOTCH3 internalized?
Yes. Both WT and CADASIL NOTCH3 proteins are endocytosed before ECD shedding and then undergo dissociation and independent trafficking of the ECD and ICD in the endosome.
Sources: PMID 40764588 · PMID 34782554 · PMID 34095881 · PMID 33894418 · PMID 33664344. AI-extracted from abstracts, so verify before citing.
NOTCH3 clinical trials
Clinical-stage (up to phase 2, any modality). Nuclens hasn't indexed trials for NOTCH3 yet. Search ClinicalTrials.gov for NOTCH3 trials.
NOTCH3 normal tissue expression
Normal-tissue expression in dose-limiting organs (kidney, liver, bone marrow, salivary glands) drives radioligand dosimetry risk. Nuclens is re-validating its normal-tissue values, so they are not shown here yet. See NOTCH3 in the Human Protein Atlas tissue atlas, and read how normal-tissue expression predicts radioligand dosimetry risk.
NOTCH3 gene essentiality (DepMap)
CRISPR knockout effect across 1258 cancer cell lines: -0.06 (not essential). Radioligands kill by radiation, not by blocking the target, so essentiality matters less than for inhibitors. A non-essential target can still be an excellent radioligand target.
Related neuroendocrine tumors radioligand targets
HER3 (ERBB3) · c-MET (MET) · SSTR2 · STEAP2 · EPCAM · ITGB6 · KIT · FAP
See all radioligand therapy targets in neuroendocrine tumors.
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Subcellular localization: UniProt via Open Targets (CC BY 4.0 / CC0). Tumor immunohistochemistry: Human Protein Atlas (CC BY-SA 4.0). Clinical trials: ClinicalTrials.gov (public domain). Gene essentiality: DepMap (CC BY 4.0). Internalization and shedding: AI-extracted from PubMed abstracts, so verify against the cited papers before relying on them. Nuclens is a first-pass triage layer, not a substitute for wet-lab validation or clinical dosimetry. Derived expression data on this page is shared under CC BY-SA 4.0.