FGFR3 alterations in bladder cancer: Sensitivity and resistance to targeted therapies

IF 20.1 1区 医学 Q1 ONCOLOGY Cancer Communications Pub Date : 2024-08-19 DOI:10.1002/cac2.12602
Maxim Noeraparast, Katarina Krajina, Renate Pichler, Dora Niedersüß-Beke, Shahrokh F Shariat, Viktor Grünwald, Sascha Ahyai, Martin Pichler
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Abstract

In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non-muscle-invasive and muscle-invasive forms of the disease. FGFR3 mutations in up to half of BLCAs play a well-established role in tumorigenesis, shaping distinct tumor initiation patterns and impacting the tumor microenvironment (TME). Emphasizing the importance of considering epithelial-mesenchymal transition profile and TME status, we revisit their relevance in predicting responses to immune checkpoint inhibitors in FGFR3-mutated BLCAs. This writing highlights the initially promising yet transient efficacy of the FGFR inhibitor Erdafitinib on FGFR3-mutated BLCA, stressing the pressing need to unravel resistance mechanisms and identify co-targets for future combinatorial studies. A thorough analysis of recent preclinical and clinical evidence reveals resistance mechanisms, including secondary mutations, epigenetic alterations in pathway effectors, phenotypic heterogeneity, and population-specific variations within FGFR3 mutational status. Lastly, we discuss the potential of combinatorial treatments and concepts like synthetic lethality for discovering more effective targeted therapies against FGFR3-mutated BLCA.

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膀胱癌中的 FGFR3 改变:靶向疗法的敏感性和耐药性。
在这篇综述中,我们重新审视了成纤维细胞生长因子受体 3 (FGFR3) 在膀胱癌 (BLCA) 中的关键作用,强调了它在非肌肉浸润性和肌肉浸润性膀胱癌中的普遍性。多达半数的膀胱癌患者体内的 FGFR3 基因突变在肿瘤发生过程中发挥了公认的作用,形成了独特的肿瘤起始模式并影响了肿瘤微环境(TME)。我们强调了考虑上皮-间质转化特征和TME状态的重要性,并重新审视了它们在预测FGFR3突变BLCA对免疫检查点抑制剂的反应中的相关性。这篇文章强调了FGFR抑制剂Erdafitinib对FGFR3突变的BLCA最初具有良好但短暂的疗效,强调了揭示耐药机制并为未来的联合研究确定共同靶点的迫切需要。对近期临床前和临床证据的深入分析揭示了耐药机制,包括继发性突变、通路效应因子的表观遗传学改变、表型异质性以及 FGFR3 突变状态下的人群特异性变化。最后,我们讨论了组合疗法和合成致死等概念的潜力,以发现针对 FGFR3 突变的 BLCA 的更有效的靶向疗法。
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来源期刊
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
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