# BTK (Bruton tyrosine kinase)

Source: https://onco.cc/targets/btk/  
OnCo record `btk` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The signalling enzyme that B-cell cancers use to survive. Blocking it turned chronic lymphocytic leukaemia into a disease controlled by a daily pill.

## Summary

BTK sits downstream of the B-cell receptor. Covalent inhibitors (ibrutinib 2014, acalabrutinib, zanubrutinib) bind C481; resistance via C481S mutations is overcome by the non-covalent inhibitor pirtobrutinib (full approval December 2025) and, in phase 3, by BTK degraders (BGB-16673 vs pirtobrutinib in CaDAnCe-304). Standard in CLL, mantle cell lymphoma, Waldenström, and marginal zone lymphoma. Next-generation BTK inhibitors reduced the atrial fibrillation and bleeding seen with ibrutinib.

## Fields

- Kind: Target
- Last checked: 2026-09-07
- Tags: kinase
- Symbol: BTK
- Class: kinase
- 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).
- Where found: CLL/SLL; Mantle cell lymphoma; Waldenström macroglobulinaemia; Marginal zone lymphoma

## Notes

- Lymphoma, Chronic active B-cell receptor signalling, and BTK: The B-cell receptor normally signals only when it meets antigen. In activated B-cell-like lymphoma it signals continuously: the receptors cluster in the membrane and diffuse slowly, exactly as they do in an antigen-stimulated normal B cell, and knocking down IgM, Ig-kappa, CD79A, CD79B or BTK kills the cell. The signal runs CD79a/b to SYK to BTK to PLC-gamma-2 to protein kinase C beta to the CARD11-BCL10-MALT1 complex and into NF-kB. Mutations of the ITAM module of CD79B raise surface receptor expression and blunt LYN, the feedback brake (Davis 2010). Frequency: Mutations of the first ITAM tyrosine of CD79B in 18% of activated B-cell-like cases, frequent in that subtype and rare in other diffuse large B-cell lymphomas, absent from Burkitt and MALT lymphoma; activating CARD11 mutations in roughly 10% of activated B-cell-like cases (Davis 2010). What it changes about treatment: This is the one pathway in lymphoma where the biology picks the drug today. BTK inhibitors are standard in mantle cell lymphoma and Waldenstrom macroglobulinaemia and have activity in primary CNS lymphoma and in the MCD genetic subtype of diffuse large B-cell lymphoma; they do little in germinal-centre disease.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Bruton%27s_tyrosine_kinase
- Wikipedia: https://en.wikipedia.org/wiki/Bruton%27s_tyrosine_kinase
- Davis et al., Nature 2010: chronic active B-cell receptor signalling in diffuse large B-cell lymphoma: https://doi.org/10.1038/nature08638

## Connected records

- cancers: [Chronic lymphocytic leukaemia](https://onco.cc/cancers/cll/), [Chronic lymphocytic leukaemia, first treatment](https://onco.cc/cancers/cll-treatment-naive/), [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Follicular lymphoma](https://onco.cc/cancers/follicular-lymphoma/), [Hairy cell leukaemia](https://onco.cc/cancers/hairy-cell-leukemia/), [Mantle cell lymphoma](https://onco.cc/cancers/mantle-cell-lymphoma/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [Primary CNS lymphoma](https://onco.cc/cancers/primary-cns-lymphoma/), [Relapsed or refractory chronic lymphocytic leukaemia](https://onco.cc/cancers/cll-relapsed/), [Richter transformation of chronic lymphocytic leukaemia](https://onco.cc/cancers/richter-transformation-cll/), [Waldenström macroglobulinaemia](https://onco.cc/cancers/waldenstrom/)
- drugs: [Acalabrutinib](https://onco.cc/drugs/acalabrutinib/), [Bexobrutideg](https://onco.cc/drugs/bexobrutideg/), [BGB-16673](https://onco.cc/drugs/bgb-16673/), [Ibrutinib](https://onco.cc/drugs/ibrutinib/), [Nemtabrutinib](https://onco.cc/drugs/nemtabrutinib/), [Orelabrutinib](https://onco.cc/drugs/orelabrutinib/), [Pirtobrutinib](https://onco.cc/drugs/pirtobrutinib/), [Zanubrutinib](https://onco.cc/drugs/zanubrutinib/)
- pathways: [B-cell receptor / BTK signalling (to NF-κB)](https://onco.cc/pathways/bcr-signalling/), [Inflammation & NF-κB](https://onco.cc/pathways/inflammation-nfkb/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/), [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/), [Ubiquitin-proteasome system & protein homeostasis](https://onco.cc/pathways/ubiquitin-proteasome-system/)
- trials: [A Study of BR Alone Versus in Combination With Acalabrutinib in Subjects With Previously Untreated MCL](https://onco.cc/trials/nct02972840/), [ALPINE](https://onco.cc/trials/alpine/), [AMPLIFY](https://onco.cc/trials/amplify/), [ARCHED](https://onco.cc/trials/arched/), [BELLWAVE-011](https://onco.cc/trials/bellwave-011/), [BRUIN CLL-321](https://onco.cc/trials/bruin-cll-321/), [CaDAnCe-304](https://onco.cc/trials/cadance-304/), [CAPTIVATE](https://onco.cc/trials/captivate/), [CELESTIAL-TNCLL](https://onco.cc/trials/celestial-tncll/), [CLL13 / GAIA](https://onco.cc/trials/cll13-gaia/), [ELEVATE-TN](https://onco.cc/trials/elevate-tn/), [ENRICH](https://onco.cc/trials/enrich/), [GLOW](https://onco.cc/trials/glow/), [RESOLVE](https://onco.cc/trials/resolve/), [RESONATE](https://onco.cc/trials/resonate/), [ROSEWOOD](https://onco.cc/trials/rosewood/), [SEQUOIA](https://onco.cc/trials/sequoia/), [SHINE](https://onco.cc/trials/shine/)
- pairings: [BTK inhibitor + venetoclax, fixed duration](https://onco.cc/pairings/btki-plus-venetoclax-fixed-duration/)
- ideas: [Assign first-line treatment in diffuse large B-cell lymphoma by genetic subtype, not by a three-antibody stain](https://onco.cc/ideas/lymphoma-ev-genetic-subtype-directed-first-line/), [BTK degraders to pre-empt resistance in frontline CLL](https://onco.cc/ideas/idea-btk-degrader-frontline/), [Fixed-duration, chemotherapy-free first-line treatment for the indolent lymphomas](https://onco.cc/ideas/lymphoma-ev-fixed-duration-chemotherapy-free-first-line/)
- biomarkers: [BTK resistance mutations: C481S, and L528W and T474I after the non-covalent inhibitors](https://onco.cc/biomarkers/btk-c481s/), [CD79B ITAM mutation](https://onco.cc/biomarkers/cd79b-itam-mutation/)
- key papers: [Acalabrutinib plus bendamustine-rituximab in untreated mantle cell lymphoma](https://onco.cc/key-papers/paper-echo-acalabrutinib-bendamustine-rituximab-mantle-cell-jco-2025/), [AMPLIFY: fixed-duration acalabrutinib plus venetoclax, with or without obinutuzumab, versus chemo-immunotherapy in fit CLL patients](https://onco.cc/key-papers/paper-amplify-acalabrutinib-venetoclax-nejm-2025/), [ELEVATE-TN: acalabrutinib, alone or with obinutuzumab, against chemo-immunotherapy in untreated CLL](https://onco.cc/key-papers/paper-elevate-tn-acalabrutinib-lancet-2020/), [Genetics and pathogenesis of diffuse large B-cell lymphoma](https://onco.cc/key-papers/paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018/), [Ibrutinib and rituximab versus immunochemotherapy in patients with previously untreated mantle cell lymphoma (ENRICH): a randomised, open-label, phase 2/3 superiority trial](https://onco.cc/key-papers/paper-enrich-ibrutinib-rituximab-mantle-cell-lancet-2025/), [Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma](https://onco.cc/key-papers/paper-shine-ibrutinib-bendamustine-rituximab-mantle-cell-nejm-2022/), [Randomized phase III trial of ibrutinib and R-CHOP in non-germinal centre B-cell diffuse large B-cell lymphoma (PHOENIX)](https://onco.cc/key-papers/paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019/), [ROSEWOOD: a phase II randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma](https://onco.cc/key-papers/paper-rosewood-zanubrutinib-obinutuzumab-follicular-jco-2023/), [ZUMA-2: brexu-cel CAR-T for mantle cell lymphoma that has failed BTK inhibitors](https://onco.cc/key-papers/paper-zuma-2-brexu-cel-mantle-cell-nejm-2020/)
- roadmaps: [Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting](https://onco.cc/roadmaps/lymphoma-roadmap/), [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)
- targets: [HCK kinase](https://onco.cc/targets/hck/)
- people: [Louis M. Staudt](https://onco.cc/people/louis-staudt/)
- terms: [BTK C481S, PLCG2 and BCL2 G101V resistance mutations](https://onco.cc/terms/btki-bcl2i-resistance-mutations/), [MYD88 L265P and CXCR4 mutations](https://onco.cc/terms/myd88-l265p/)
- institutions: [The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute](https://onco.cc/institutions/osu-james/)
- companies: [InnoCare Pharma](https://onco.cc/companies/innocare/)

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JSON: https://onco.cc/api/v1/entities/btk.json