{"entity":{"id":"paper-montoya-science","kind":"paper","name":"Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127","aka":[],"tldr":"Paper cited by one idea page, indexed on Europe PMC as PubMed record 38301010 and published in Science; the citing page links this DOI, which is how the record was matched.","summary":"Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.\n\nIndexed on Europe PMC as PubMed record 38301010 (DOI 10.1126/science.adi5798). Matched by DOI alone: one idea page cites this DOI among its external links (the pages are listed under Related), and this page was written so that the citation resolves inside OnCo. No figure has been checked by an editor.","asOf":"2026-09-22","links":[{"label":"Science 2024","url":"https://doi.org/10.1126/science.adi5798"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/38301010/"},{"label":"Europe PMC","url":"https://europepmc.org/article/MED/38301010"}],"tags":["europepmc-ingest"],"related":["idea-btk-degrader-frontline"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["science"],"dependsOn":[],"notes":[],"journal":"Science","year":2024,"doi":"10.1126/science.adi5798","pmid":"38301010","authors":"Montoya S, Bourcier J, Noviski M, et al.","paperType":"observational","findings":[],"whatItMeans":"One idea page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.","caveats":["Matched to the citing OnCo records by DOI alone; the summary reproduces the Europe PMC abstract and no figure has been verified against the full paper."]},"route":"/key-papers/paper-montoya-science/","neighbours":{"idea":[{"id":"idea-btk-degrader-frontline","kind":"idea","name":"BTK degraders to pre-empt resistance in frontline CLL","route":"/ideas/idea-btk-degrader-frontline/"}],"journal":[{"id":"science","kind":"journal","name":"Science","route":"/journals/science/"}]}}