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BTK<jats:sup>Cys481<\/jats:sup> mutations are associated with cBTK\u2010i acquired resistance and are accompanied by reactivation of ERK1\/2 that promotes inflammatory cytokine secretion and paracrine\u2010mediated resistance of BTK wild\u2010type (BTK<jats:sup>WT<\/jats:sup>) tumour cells. Pirtobrutinib is a non\u2010covalent BTK\u2010inhibitor that binds at non\u2010BTK<jats:sup>Cys481<\/jats:sup> sites. We show that pirtobrutinib blocked p\u2010ERK1\/2, ERK1\/2\u2010driven inflammatory cytokines, and overcame paracrine\u2010mediated resistance in <jats:italic>MYD88<\/jats:italic><jats:sup>Mut<\/jats:sup> lymphoma cells expressing mutated BTK<jats:sup>Cys481<\/jats:sup>. Our results provide important mechanistic insights for the activity of pirtobrutinib in <jats:italic>MYD88<\/jats:italic><jats:sup>Mut<\/jats:sup> lymphomas carrying BTK<jats:sup>Cys481<\/jats:sup> mutations.<\/jats:p>","DOI":"10.1111\/bjh.19756","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T01:24:28Z","timestamp":1726709068000},"page":"1866-1872","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["ERK1\/2 pro\u2010survival signalling is suppressed by pirtobrutinib in ibrutinib\u2010resistant <i>MYD88<\/i>\u2010mutated lymphoma cells"],"prefix":"10.1111","volume":"205","author":[{"given":"M.","family":"Munshi","sequence":"first","affiliation":[{"name":"Dana Farber Cancer Institute  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X.","family":"Liu","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Kofides","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Tsakmaklis","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1689-1691","authenticated-orcid":false,"given":"Z. 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