TROP2
A protein that sits on the outside of many cancer cells far more than on normal cells, making it a good address for delivering drugs. This dossier gathers the 4 products (2 approved), 11 trials, 2 pathways and 7 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
Biology
Regulates calcium signalling and cell adhesion; overexpression correlates with poor prognosis. Expression is heterogeneous within tumours, which limits the value of IHC selection. Internalises on antibody binding and traffics to lysosomes, which is what makes it a good ADC target.
- Triple-negative breast cancer (~80-90% express)
- HR+ breast cancer
- NSCLC
- Urothelial carcinoma
- Gastric, pancreatic, endometrial cancers
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsHow common it is, by cancer
Full matrix →| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Triple-negative breast cancer | 80-90% | IHC, any/moderate-high expression | ASCENT benefit was independent of TROP2 IHC level | PMC |
| Bladder & urothelial cancer | 80-90% | IHC, any expression | PMC | |
| HR-positive / HER2-negative breast cancer | 75-90% | IHC, any expression | PMC | |
| Non-small-cell lung cancer | 60-70% | IHC, moderate-high | Adenocarcinoma and squamous | PMC |
| Pancreatic ductal adenocarcinoma | 50% | IHC, any expression | Approximate; heterogeneous | PMC |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Products by modality and phase
Browse products →| Modality | Approved | Phase 3 | Phase 1 |
|---|---|---|---|
| ADC 3 | — | ||
| Bispecific ADC 1 | — | — |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| ASCENT-03 NCT05382299 | 3 | Positive | First-line metastatic TNBC, not candidates for PD-1 inhibitors: sacituzumab govitecan vs chemotherapy | PFS HR 0.62. | |
| ASCENT-04 / KEYNOTE-D19 NCT05382286 | 3 | Positive | First-line PD-L1+ (CPS ≥10) metastatic TNBC: sacituzumab govitecan + pembrolizumab vs chemotherapy + pembrolizumab | PFS HR 0.65; PFS2 improved. | |
| TROPION-Breast02 NCT05374512 | 3 | Positive | First-line metastatic TNBC, not candidates for PD-1/PD-L1: Dato-DXd vs chemotherapy | OS 23.7 vs 18.7 months; PFS also improved. | |
| TROPION-Breast01 NCT05104866 | 3 | Mixed | HR+/HER2- metastatic breast cancer after endocrine and 1-2 chemotherapies: Dato-DXd vs chemotherapy | PFS HR 0.63; OS HR 1.01. | |
| TROPION-Lung01 NCT04656652 | 3 | Mixed | Previously treated advanced NSCLC: Dato-DXd vs docetaxel | PFS HR 0.75; OS HR 0.94. | |
| TROPiCS-02 NCT03901339 | 3 | Positive | HR+/HER2- metastatic breast cancer after endocrine therapy, CDK4/6, and 2-4 chemotherapies: sacituzumab govitecan vs chemotherapy | OS 14.4 vs 11.2 months, HR 0.79. | |
| ASCENT NCT02574455 | 3 | Positive | Pretreated metastatic TNBC: sacituzumab govitecan vs chemotherapy | OS 12.1 vs 6.7 months, HR 0.48. | |
| ASCENT-05 / OptimICE-RD (AFT-65, GBG 119, NSABP B-63) NCT05633654 | 3 | Active | Stage II–III TNBC with residual invasive disease after neoadjuvant therapy and surgery: adjuvant sacituzumab govitecan + pembrolizumab vs pembrolizumab ± capecitabine | ||
| TROPION-Breast03 NCT05629585 | 3 | Active | Stage I–III TNBC with residual invasive disease after neoadjuvant therapy: adjuvant Dato-DXd ± durvalumab vs investigator's choice (capecitabine, pembrolizumab, or both) | ||
| TROPION-Breast05 NCT06103864 | 3 | Recruiting | First-line PD-L1+ metastatic TNBC: Dato-DXd ± durvalumab vs pembrolizumab + chemotherapy | ||
| TROPION-Lung05 NCT04484142 | 2 | Positive | Actionable-genomic-alteration NSCLC after targeted therapy and platinum: datopotamab deruxtecan single arm | ORR 43.6% in EGFR-mutant disease. |
Resistance routes that involve this target
Unaddressed routes →Mutation of the cysteine that osimertinib binds covalently; abolishes drug binding while EGFR stays active.
- Fourth-generation allosteric EGFR inhibitors (in trials); amivantamab-based regimens
- ADCs that bypass genotype: Dato-DXd, HER3-DXd, iza-bren
TOP1 mutations (e.g., E418K) or reduced expression prevent trapping of the cleavage complex.
- Switch payload class (tubulin, DNA-crosslinking, degrader) rather than antigen
- Radioconjugates against the same antigen
Schlafen-11 is required for replication-stress-induced death; its epigenetic silencing confers resistance to TOP1 (and platinum) agents.
- ATR/CHK1 inhibitors re-sensitise SLFN11-low cells preclinically
- EZH2 inhibition to restore SLFN11 (preclinical)
SN-38 is an ABCG2 substrate; DXd and MMAE are ABCB1 substrates; mesenchymal states upregulate both.
- Payloads reported to be weaker efflux substrates (sac-TMT's belotecan derivative)
- Efflux-agnostic modalities: radiation, T-cell engagers
Reduced HER2 or TROP2 surface expression after treatment; less frequent than payload resistance for HER2-low disease.
- Antigen PET to detect loss and pick the next target
- Bispecific ADCs hitting two antigens
Defective endocytosis or lysosomal cathepsin activity limits payload release.
- Biparatopic antibodies that force receptor clustering (zanidatamab-type)
Without RB, CDK4/6 inhibition cannot arrest the cell cycle.
- Switch to chemotherapy or ADCs (T-DXd for HER2-low, sacituzumab, Dato-DXd)
Pathways where it is a node
Pathway-to-drug matrix →- DNA replication & origin licensingNode: TOP1 (chemo, ADC payloads) · 3 druggable nodes
Before a cell divides it must copy three billion letters of DNA exactly once. It does this by 'licensing' thousands of start points in advance and then firing them in waves. Cancers fire too many too fast, and many chemotherapies work by starving or jamming the copying machinery.
Which nodes have drugs → - Drug efflux pumps (ABC transporters)Node: Non-substrate payloads (DXd) · 2 druggable nodes
Cancer cells can install pumps in their outer membrane that throw chemotherapy back out as fast as it comes in. The same pumps guard the gut, brain and bone marrow in healthy tissue, which is why blocking them failed as a strategy and why drug designers now choose payloads the pumps cannot grip.
Which nodes have drugs →
Companion diagnostics and assays
Assay registry →No companion diagnostic in the registry measures this target.
Preclinical models
All models →| Cell line | Identifiers | Why it is used |
|---|---|---|
| MDA-MB-468 | CVCL_0419 · ACH-000849 | TROP2-high TNBC. |
| HCC1806 | CVCL_1258 · ACH-000624 | TROP2-high TNBC. |
| BxPC-3 | CVCL_0186 · ACH-000535 | TROP2-high pancreatic. |
| NCI-H1975 | CVCL_1511 · ACH-000587 | TROP2-positive lung; Dato-DXd model. |
| Calu-3 | CVCL_0609 · ACH-000392 | TROP2-positive lung. |
| MDA-MB-231 | CVCL_0062 · ACH-000768 | TROP2-low comparator. |
Open questions
All open questions →- 01
Is there any biomarker (IHC, PET, quantitative continuous scoring) that predicts who benefits from a TROP2 ADC?
translationalresearchWhy unresolved. TROP2 ADCs are given without testing because IHC did not separate responders in ASCENT or TROPION-Breast01; TROPION-Lung01 reported a computational membrane-ratio score retrospectively but it is unvalidated.
What would answer it. Prospective validation of a quantitative TROP2 score or a TROP2 PET tracer against progression-free survival in a randomised ADC trial.
Source: ASCENT, NEJM 2021
Ideas and companies
Key papers and the live literature
Preprints →- TROPION-Breast01: datopotamab deruxtecan versus chemotherapy in pretreated hormone-receptor-positive breast cancer, and why a PFS win did not translate to survival · Journal of Clinical Oncology 2024
- ASCENT: sacituzumab govitecan doubles survival in heavily pretreated metastatic triple-negative breast cancer · New England Journal of Medicine 2021
Query for this target: (TITLE:"TROP2" OR ABSTRACT:"TROP2" OR TITLE:"TACSTD2" OR ABSTRACT:"TACSTD2") 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 TROP2, not a curated reading list.
Export
The dossier as machine-readable JSON: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/trop2.json. Licence CC BY 4.0.