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Several targeted therapies have been approved for tumours harbouring <jats:italic>NTRK<\/jats:italic> fusions and a new generation of TRK inhibitors has already been developed due to acquired resistance. We established a patient\u2010derived <jats:italic>LMNA<\/jats:italic>::<jats:italic>NTRK1<\/jats:italic>\u2010rearranged soft\u2010tissue sarcoma cell model <jats:italic>ex vivo<\/jats:italic> with an acquired resistance to targeted TRK inhibition. Molecular profiling of the resistant clones revealed an acquired <jats:italic>NF2<\/jats:italic> loss of function mutation that was absent in the parental cell model. Parental cells showed continuous sensitivity to TRK\u2010targeted treatment, whereas the resistant clones were insensitive. Furthermore, resistant clones showed upregulation of the MAPK and mTOR\/AKT pathways in the gene expression based on RNA sequencing data and increased sensitivity to MEK and mTOR inhibitor therapy. Drug synergy was seen using trametinib and rapamycin in combination with entrectinib. Medium\u2010throughput drug screening further identified small compounds as potential drug candidates to overcome resistance as monotherapy or in combination with entrectinib. In summary, we developed a comprehensive model of drug resistance in an <jats:italic>LMNA<\/jats:italic>::<jats:italic>NTRK1<\/jats:italic>\u2010rearranged soft\u2010tissue sarcoma and have broadened the understanding of acquired drug resistance to targeted TRK therapy. Furthermore, we identified drug combinations and small compounds to overcome acquired drug resistance and potentially guide patient care in a functional precision oncology setting. \u00a9 2024 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6282","type":"journal-article","created":{"date-parts":[[2024,4,13]],"date-time":"2024-04-13T02:45:51Z","timestamp":1712976351000},"page":"257-269","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Acquired <scp><i>NF2<\/i><\/scp> mutation confers resistance to <scp>TRK<\/scp> inhibition in an <i>ex vivo<\/i><scp><i>LMNA<\/i><\/scp>::<scp><i>NTRK1\u2010<\/i><\/scp>rearranged soft\u2010tissue sarcoma cell 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