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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 8 products (5 approved), 83 trials, 1 pathway and 4 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.
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).
| 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.
| 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.
| Modality | Approved | Phase 3 |
|---|---|---|
| Small molecule 6 | ||
| Degrader 2 | - |
| Trial | Setting | Result | Products | ||
|---|---|---|---|---|---|
| 3 | Active | A Phase 3, Randomized, Double-blind, Placebo-controlled, Multicenter Study of Bendamustine and Rituximab (BR) Alone Versus in Combination With Acalabrutinib (ACP-196) in Subjects With Previously Untreated Mantle Cell Lymphoma | Median progression-free survival 66.4 against 49.6 months (hazard ratio 0.73, p = 0.0160), with no significant overall survival difference (hazard ratio 0.86, p = 0.27). | ||
| 3 | Active | A Randomized, Multicenter, Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of Acalabrutinib Versus Chlorambucil Plus Rituximab in Subjects With Previously Untreated Chronic Lymphocytic Leukemia | - | ||
SYMPATICO NCT03112174 | 3 | Positive | Relapsed or refractory mantle cell lymphoma after one to five prior lines: ibrutinib with venetoclax or with placebo (double-blind), after a safety run-in for tumour lysis syndrome, plus an open-label treatment-naive arm of the combination in patients with TP53 mutation | Median progression-free survival 31.9 months with ibrutinib plus venetoclax against 22.1 months with ibrutinib plus placebo (hazard ratio 0.629, p 0.0024); complete response 69.2 percent in treatment-naive TP53-mutated disease. | |
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. | |
CLL12 NCT02863718 | 3 | Mixed | Asymptomatic, untreated Binet stage A chronic lymphocytic leukaemia at increased risk of early progression: ibrutinib 420 mg daily or placebo (double-blind), with a low-risk cohort followed on watch and wait | Ibrutinib delayed progression to symptomatic disease but did not improve survival: five-year overall survival 93.3 percent against 93.6 percent with placebo; watch and wait remains standard for early-stage disease. | |
TRIANGLE NCT02858258 | 3 | Positive | Previously untreated mantle cell lymphoma in patients up to 65 fit for transplant: alternating R-CHOP and R-DHAP induction followed by autologous transplant (arm A), the same with ibrutinib added to induction and as two-year maintenance (arm A+I), or ibrutinib-containing induction and maintenance without transplant (arm I) | Three-year failure-free survival 88 percent with ibrutinib added to induction, transplant and maintenance against 72 percent with standard induction and transplant (hazard ratio 0.52); transplant was not shown to be superior to an ibrutinib-containing regimen without transplant (72 against 86 percent). | |
| 3 | Active | A Randomized, Multicenter, Open-Label, Phase 3 Study of Acalabrutinib (ACP-196) Versus Investigator's Choice of Either Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Subjects With R/R Chronic Lymphocytic Leukemia | - | ||
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). | |
SHINE NCT01776840 | 3 | Mixed | Aged 65 or over with untreated mantle cell lymphoma: ibrutinib added to six cycles of bendamustine and rituximab, with rituximab maintenance | Median progression-free survival 80.6 against 52.9 months (hazard ratio 0.75, p = 0.01) with no overall survival difference. | |
| 3 | Active | A Randomized, Multicenter, Open-Label, Non-Inferiority, Phase III Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Subjects With High Risk Chronic Lymphocytic Leukemia | - | ||
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). | |
RESOLVE NCT02436668 | 3 | Negative | Untreated metastatic pancreatic ductal adenocarcinoma at sites in eight countries: ibrutinib 560 mg daily or placebo with nab-paclitaxel plus gemcitabine, double-blind, with overall survival and investigator-assessed progression-free survival as primary endpoints | Median overall survival 9.7 months with ibrutinib plus nab-paclitaxel and gemcitabine against 10.8 months with placebo (p 0.3225); progression-free survival 5.3 against 6.0 months (p below 0.0001); response 29 against 42 percent. | |
ASPEN (Waldenström macroglobulinaemia) NCT03053440 | 3 | Mixed | Waldenström macroglobulinaemia with a MYD88 mutation, untreated or relapsed: zanubrutinib against ibrutinib, with a separate cohort of MYD88 wild-type disease on zanubrutinib | Zanubrutinib did not significantly increase the complete or very good partial response rate over ibrutinib, but had markedly less cardiovascular and other toxicity; approved for Waldenström macroglobulinaemia in 2021. | |
ELEVATE-TN NCT02475681 | 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-2 NCT01722487 | 3 | Positive | Previously untreated chronic lymphocytic leukaemia or small lymphocytic lymphoma in patients aged 65 or older without 17p deletion: ibrutinib until progression against chlorambucil for up to twelve cycles | Ibrutinib improved progression-free and overall survival over chlorambucil in older patients with untreated CLL; approved for first-line CLL in March 2016. | |
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). | |
| 3 | Active | Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Acalabrutinib in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Subjects ≤75 Years With Previously Untreated Non-GCB DLBCL | - | ||
| 3 | Recruiting | A Randomized, Double-Blind, Multicenter, Placebo-Controlled Phase 3 Study of Orelabrutinib in Combination with Rituximab and Bendamustine (BR) Vs. BR in Subjects with Treatment-Naїve Mantle Cell Lymphoma | - | ||
| 3 | Recruiting | PCI-32765CAN3001: A Phase 3b, Multicenter, Open-label, PCI-32765 (Ibrutinib) Long-term Extension Study | - | ||
| 3 | Active | A Phase III Prospective, Multicenter, Randomized, Open-Label Trial of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma | - | ||
| 3 | Active | A Phase 3, Open-Label, Randomized Study of BGB-16673 Compared to Investigator's Choice in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Previously Exposed to Covalent BTK Inhibitors | - | ||
| 3 | Recruiting | A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Nemtabrutinib (MK-1026) Plus Venetoclax Versus Venetoclax Plus Rituximab in Participants With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Following at Least 1 Prior Therapy (BELLWAVE-010) | - | ||
| 3 | Active | A Phase 3, Randomized Study to Compare the Efficacy and Safety of Nemtabrutinib Versus Chemoimmunotherapy for Previously Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Without TP53 Aberrations | - | ||
| 3 | Active | A Phase 3 Open-Label, Randomized Study of Pirtobrutinib (LOXO-305) Versus Bendamustine Plus Rituximab in Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma | - | ||
| 3 | Recruiting | A Phase 3 Open-Label, Randomized Study of Pirtobrutinib (LOXO-305) Versus Ibrutinib in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN-CLL-314) | - | ||
| 3 | Active | A Phase 3 Randomized, Open-Label Multicenter Study of Zanubrutinib (BGB-3111) Plus Anti-CD20 Antibodies Versus Lenalidomide Plus Rituximab in Patients With Relapsed/Refractory Follicular or Marginal Zone Lymphoma | - | ||
| 3 | Active | An Open-label, Multi-center, Long-term Extension Study of Zanubrutinib (BGB-3111) Regimens in Patients With B-cell Malignancies | - |
Substituting the cysteine the drug binds covalently leaves the kinase active and makes inhibition reversible, so the drug no longer holds.
The kinase-dead L528W substitution and the gatekeeper T474I change the pocket rather than the covalent cysteine, so they defeat reversible inhibitors too.
R665W and L845F make B-cell receptor signalling autonomous below the kinase, so blocking BTK above them achieves nothing.
The valine substitution at glycine 101 reduces BCL-2 affinity for venetoclax about 180-fold, so the drug can no longer displace the pro-apoptotic proteins while BCL-2 keeps working.
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 →No companion diagnostic in the registry measures this target.
| 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. |
Why 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 2014Query 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.
The dossier as machine-readable JSON, at /api/v1/dossiers/btk.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-NC 4.0.