Pettitt, GA, Hurst, CD, Khan, Z et al. (7 more authors) (Cover date: February 2023) Development of resistance to FGFR inhibition in urothelial carcinoma via multiple pathways in vitro. Journal of Pathology, 259 (2). pp. 220-232. ISSN 0022-3417
Abstract
Alterations of fibroblast growth factor receptors (FGFRs) are common in bladder and other cancers and result in disrupted signalling via several pathways. 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-driven bladder cancer cell lines by long-term culture with the FGFR inhibitor PD173074 and explored mechanisms using expression profiling and whole-exome sequencing. We identified several resistance-associated molecular profiles. These included HRAS mutation in one case and reversible mechanisms resembling a drug-tolerant 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | bladder cancer; FGFR3 inhibition; resistance mechanisms; transcriptome; HRAS mutation; IGF1R; YAP/TAZ; drug tolerance |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Dentistry (Leeds) > Oral Biology (Leeds) |
Funding Information: | Funder Grant number Yorkshire Cancer Research Account Ref: 2UOLEEDS L011PhD |
Depositing User: | Symplectic Publications |
Date Deposited: | 01 Dec 2022 15:33 |
Last Modified: | 23 Jan 2023 14:07 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/path.6034 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:193547 |