BTK (Bruton tyrosine kinase)
The signalling enzyme that B-cell cancers use to survive. Blocking it turned chronic lymphocytic leukaemia into a disease controlled by a daily pill. This dossier gathers the 6 products (4 approved), 12 trials, 1 pathway and 0 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
TEC-family cytoplasmic tyrosine kinase; phosphorylates PLCγ2 after BCR engagement. Resistance mutations: C481S/R/F (covalent), T474I and L528W (non-covalent, also confer cross-resistance).
- CLL/SLL
- Mantle cell lymphoma
- Waldenström macroglobulinaemia
- Marginal zone lymphoma
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsHow common it is, by cancer
Full matrix →| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Chronic lymphocytic leukaemia | 100% | pathway dependence (BCR signalling), not a mutation | Target is wild-type; resistance mutations arise on treatment |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Mutation hotspots and which drugs address them
| Residue | Kind | How common | What it does | Addressed by | Defeats | Source |
|---|---|---|---|---|---|---|
| C481S / C481R / C481F 481 | Resistance | The dominant mutation at progression on covalent BTK inhibitors in CLL | Removes the cysteine the covalent drugs bond to. Non-covalent pirtobrutinib and BTK degraders do not need it. | Woyach et al., NEJM 2014 | ||
| T474I (gatekeeper) and L528W (kinase-dead) 528 | Resistance | not sourced | Emerging after non-covalent inhibitors and after zanubrutinib; L528W abolishes kinase activity yet the scaffold still signals, which is why degraders that remove the whole protein are being tested. | Wang et al., Blood 2022 (pirtobrutinib resistance) | ||
| PLCG2 (downstream, not BTK) 659 | Other | not sourced | Shown for context: gain-of-function PLCG2 mutations bypass BTK entirely, so no BTK-directed agent works. | — | Woyach et al., NEJM 2014 |
Frequencies are quoted from the source on each row; a blank means no figure was sourced, not that it is rare. Domain boundaries are approximate. Sources for the map: COSMIC: BTK.
Products by modality and phase
Browse products →| Modality | Approved | Phase 3 |
|---|---|---|
| Small molecule 5 | ||
| Degrader 1 | — |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| AMPLIFY NCT03836261 | 3 | Positive | Fit, previously untreated CLL without del(17p)/TP53: fixed-duration acalabrutinib + venetoclax (AV) or + obinutuzumab (AVO) vs FCR/BR chemoimmunotherapy | 3-year PFS 76.5% (AV) / 83.1% (AVO) vs 66.5%. | |
| BRUIN CLL-321 NCT04666038 | 3 | Positive | Relapsed/refractory CLL/SLL after a covalent BTK inhibitor: pirtobrutinib vs investigator's choice (idelalisib-rituximab or bendamustine-rituximab) | PFS 11.2 vs 8.7 months; HR 0.58. | |
| CLL13 / GAIA NCT02950051 | 3 | Positive | Fit, previously untreated CLL without del(17p)/TP53: chemoimmunotherapy (FCR/BR) vs venetoclax-rituximab vs venetoclax-obinutuzumab vs venetoclax-obinutuzumab-ibrutinib | 5-year PFS 81.3% (GIV), 69.8% (GV), 57.4% (RV), 50.7% (CIT). | |
| ALPINE NCT03734016 | 3 | Positive | Relapsed or refractory CLL/SLL: zanubrutinib vs ibrutinib | PFS HR 0.65; AF 5.2% vs 13.3%. | |
| SEQUOIA NCT03336333 | 3 | Positive | Previously untreated CLL/SLL unsuitable for FCR: zanubrutinib vs bendamustine-rituximab (cohort 1); zanubrutinib in del(17p) (arm C); zanubrutinib + venetoclax (arm D) | PFS HR 0.42 vs BR; 5-year PFS 72.2% in del(17p). | |
| GLOW NCT03462719 | 3 | Positive | Previously untreated CLL, age ≥65 or with comorbidities, no del(17p)/TP53: fixed-duration ibrutinib + venetoclax vs chlorambucil + obinutuzumab | PFS HR 0.216; OS HR 0.487 (4-year). | |
| ELEVATE-TN NCT02475097 | 3 | Positive | Previously untreated CLL, age ≥65 or with comorbidities: acalabrutinib ± obinutuzumab vs chlorambucil + obinutuzumab | 6-year median PFS not reached vs 27.8 months; OS HR 0.62 (A+O). | |
| RESONATE NCT01578707 | 3 | Positive | Relapsed or refractory CLL/SLL: ibrutinib vs ofatumumab | PFS HR 0.22; median PFS 44.1 vs 8.1 months (6-year). | |
| BELLWAVE-011 NCT06136559 | 3 | Recruiting | Previously untreated CLL/SLL: nemtabrutinib vs investigator's choice of ibrutinib or acalabrutinib | ||
| CaDAnCe-304 | 3 | Recruiting | Relapsed/refractory CLL/SLL after a covalent BTK inhibitor: BTK degrader BGB-16673 vs pirtobrutinib | ||
| CELESTIAL-TNCLL NCT06073821 | 3 | Active | Previously untreated CLL/SLL: fixed-duration sonrotoclax + zanubrutinib vs venetoclax + obinutuzumab | ||
| CAPTIVATE NCT02910583 | 2 | Positive | Previously untreated CLL, age ≤70: 3 cycles ibrutinib lead-in then 12 cycles ibrutinib + venetoclax (fixed-duration cohort n=159; MRD-guided cohort n=164) | CR 55%; uMRD 77%; 4-year PFS ~79%. |
Resistance routes that involve this target
Unaddressed routes →The resistance atlas has no route that names this target.
Pathways where it is a node
Pathway-to-drug matrix →- Inflammation & NF-κBNode: BCR → BTK (lymphoma) · 1 druggable nodes
Chronic inflammation is soil for cancer: it feeds growth signals, DNA damage, and immune suppression. The NF-κB switch inside cells is the master relay, and colitis, hepatitis, and H. pylori gastritis are the clinical proof.
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 |
|---|---|---|
| TMD8 | CVCL_A442 | ABC-DLBCL, CD79B mutant; ibrutinib-sensitive with C481S resistant derivatives. |
| HBL-1 | CVCL_4213 | ABC-DLBCL. |
| OCI-LY10 | CVCL_8795 · ACH-001146 | ABC-DLBCL, MYD88 L265P. |
| REC-1 | CVCL_1884 · ACH-000068 | Mantle-cell lymphoma, ibrutinib-sensitive. |
| MEC-1 | CVCL_1870 · ACH-000405 | CLL-derived line. |
- Eμ-TCL1 (TCL1 transgene) Bichi et al., PNAS 2002
Open questions
All open questions →- 01
Do BTK degraders outperform non-covalent inhibitors once C481S, T474I or L528W mutations have appeared, and could they replace inhibitors in front line?
clinicalindustryWhy unresolved. Pirtobrutinib is active against C481S but selects kinase-dead L528W; degraders such as BGB-16673 remove the scaffold and are active preclinically against every known mutation, with early clinical responses.
What would answer it. CaDAnCe-304 (degrader versus pirtobrutinib) and front-line trials with fixed-duration combinations.
Source: Woyach et al., NEJM 2014
Ideas and companies
Key papers and the live literature
Preprints →- AMPLIFY: fixed-duration acalabrutinib plus venetoclax, with or without obinutuzumab, versus chemo-immunotherapy in fit CLL patients · New England Journal of Medicine 2025
- ELEVATE-TN: acalabrutinib, alone or with obinutuzumab, against chemo-immunotherapy in untreated CLL · The Lancet 2020
- ZUMA-2: brexu-cel CAR-T for mantle cell lymphoma that has failed BTK inhibitors · New England Journal of Medicine 2020
Query for this target: (TITLE:"BTK" OR ABSTRACT:"BTK" OR TITLE:"Bruton tyrosine kinase" OR ABSTRACT:"Bruton tyrosine kinase") 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 BTK (Bruton tyrosine kinase), 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/btk.json. Licence CC BY 4.0.