Translational Oncology, II. Med Clinics Hematology and Oncology, Augsburg, Germany.
Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
Cancer Commun (Lond). 2024 Oct;44(10):1189-1208. doi: 10.1002/cac2.12602. Epub 2024 Aug 19.
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.
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，强调其在非肌肉浸润性和肌肉浸润性疾病中的普遍存在。高达一半的 BLCA 中存在 FGFR3 突变，在肿瘤发生中起着既定的作用，形成不同的肿瘤起始模式，并影响肿瘤微环境（TME）。强调考虑上皮-间充质转化谱和 TME 状态的重要性，我们重新审视它们在预测 FGFR3 突变型 BLCA 对免疫检查点抑制剂反应中的相关性。本文强调了 FGFR 抑制剂 Erdafitinib 在 FGFR3 突变型 BLCA 中最初有希望但短暂的疗效，强调迫切需要揭示耐药机制并为未来的联合研究确定共同靶点。对最近的临床前和临床证据的全面分析揭示了耐药机制，包括继发性突变、途径效应物的表观遗传改变、表型异质性以及 FGFR3 突变状态的人群特异性变异。最后，我们讨论了联合治疗的潜力和合成致死性等概念，以发现针对 FGFR3 突变型 BLCA 的更有效的靶向治疗方法。
