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. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
摘要：
成纤维细胞生长因子受体(FGFR)的改变在膀胱和其他癌症中是常见的,并且通过几种途径导致信号传导中断。靶向FGFRs的治疗药物现在已经进入临床，但是,与许多癌症疗法一样，抗性在大多数情况下发展。为了模拟这个，通过与FGFR抑制剂PD173074长期培养,我们获得了两种FGFR驱动的膀胱癌细胞系的耐药亚系,并利用表达谱分析和全外显子组测序探索了其机制.我们确定了几种抗性相关的分子谱。其中包括在一种情况下的HRAS突变和在其他情况下类似于药物耐受性表型的可逆机制。一种抗性衍生物中IGF1R表达上调与对林西替尼的敏感性相关，另一种抗性衍生物中YAP/TAZ特征对YAP抑制剂CA3的敏感性上调。然而,其他潜在治疗靶点的上调并不表示敏感性。总的来说,耐药机制的异质性和坚持状态的共性对个性化治疗提出了相当大的挑战.然而，耐药的可逆性可能表明某些患者因疾病复发而中断治疗或再治疗而获益.©2022作者由JohnWiley＆SonsLtd代表英国和爱尔兰病理学会出版的病理学杂志。
