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Therapeutics that target FGFRs have now entered the clinic, but, in common with many cancer therapies, resistance develops in most cases. To model this, we derived resistant sublines of two FGFR\u2010driven bladder cancer cell lines by long\u2010term culture with the FGFR inhibitor PD173074 and explored mechanisms using expression profiling and whole\u2010exome sequencing. We identified several resistance\u2010associated molecular profiles. These included <jats:italic>HRAS<\/jats:italic> mutation in one case and reversible mechanisms resembling a drug\u2010tolerant persister phenotype in others. Upregulated IGF1R expression in one resistant derivative was associated with sensitivity to linsitinib and a profile with upregulation of a YAP\/TAZ signature to sensitivity to the YAP inhibitor CA3 in another. However, upregulation of other potential therapeutic targets was not indicative of sensitivity. Overall, the heterogeneity in resistance mechanisms and commonality of the persister state present a considerable challenge for personalised therapy. Nevertheless, the reversibility of resistance may indicate a benefit from treatment interruptions or retreatment following disease relapse in some patients. \u00a9 2022 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.6034","type":"journal-article","created":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T00:09:32Z","timestamp":1668643772000},"page":"220-232","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Development of resistance to <scp>FGFR<\/scp> inhibition in urothelial carcinoma via multiple pathways <i>in vitro<\/i>"],"prefix":"10.1002","volume":"259","author":[{"given":"Geoffrey A","family":"Pettitt","sequence":"first","affiliation":[{"name":"Division of Molecular Medicine, Leeds Institute of Medical Research at St James's St James's University 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