Université Paris-Saclay, Gustave Roussy, Inserm U981, Villejuif, France.
Département d'Innovation Thérapeutique (DITEP), Gustave Roussy, Villejuif, France.
Cancer Discov. 2023 Sep 6;13(9):1998-2011. doi: 10.1158/2159-8290.CD-22-1441.
Several fibroblast growth factor receptor (FGFR) inhibitors are approved or in clinical development for the treatment of FGFR-driven urothelial cancer, and molecular mechanisms of resistance leading to patient relapses have not been fully explored. We identified 21 patients with FGFR-driven urothelial cancer treated with selective FGFR inhibitors and analyzed postprogression tissue and/or circulating tumor DNA (ctDNA). We detected single mutations in the FGFR tyrosine kinase domain in seven (33%) patients (FGFR3 N540K, V553L/M, V555L/M, E587Q; FGFR2 L551F) and multiple mutations in one (5%) case (FGFR3 N540K, V555L, and L608V). Using Ba/F3 cells, we defined their spectrum of resistance/sensitivity to multiple selective FGFR inhibitors. Eleven (52%) patients harbored alterations in the PI3K-mTOR pathway (n = 4 TSC1/2, n = 4 PIK3CA, n = 1 TSC1 and PIK3CA, n = 1 NF2, n = 1 PTEN). In patient-derived models, erdafitinib was synergistic with pictilisib in the presence of PIK3CA E545K, whereas erdafitinib-gefitinib combination was able to overcome bypass resistance mediated by EGFR activation.
In the largest study on the topic thus far, we detected a high frequency of FGFR kinase domain mutations responsible for resistance to FGFR inhibitors in urothelial cancer. Off-target resistance mechanisms involved primarily the PI3K-mTOR pathway. Our findings provide preclinical evidence sustaining combinatorial treatment strategies to overcome bypass resistance. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949.
已有几种成纤维细胞生长因子受体 (FGFR) 抑制剂被批准或处于临床开发阶段，用于治疗 FGFR 驱动的尿路上皮癌，但导致患者复发的耐药分子机制尚未完全阐明。我们鉴定了 21 名接受选择性 FGFR 抑制剂治疗的 FGFR 驱动性尿路上皮癌患者，并分析了进展后组织和/或循环肿瘤 DNA (ctDNA)。我们在 7 名（33%）患者的 FGFR 酪氨酸激酶结构域中检测到单突变（FGFR3 N540K、V553L/M、V555L/M、E587Q；FGFR2 L551F），在 1 名（5%）患者中检测到多个突变（FGFR3 N540K、V555L 和 L608V）。使用 Ba/F3 细胞，我们确定了它们对多种选择性 FGFR 抑制剂的耐药/敏感性谱。11 名（52%）患者存在 PI3K-mTOR 通路改变（n = 4 TSC1/2、n = 4 PIK3CA、n = 1 TSC1 和 PIK3CA、n = 1 NF2、n = 1 PTEN）。在患者衍生模型中，在存在 PIK3CA E545K 的情况下，erdafitinib 与 pictilisib 具有协同作用，而 erdafitinib-gefitinib 联合能够克服由 EGFR 激活介导的旁路耐药。
在迄今为止关于该主题的最大研究中，我们检测到 FGFR 激酶结构域突变的高频率，这些突变导致对尿路上皮癌中 FGFR 抑制剂的耐药性。非靶向耐药机制主要涉及 PI3K-mTOR 通路。我们的研究结果提供了克服旁路耐药的组合治疗策略的临床前证据。请参阅 Tripathi 等人的相关评论，第 1964 页。本文是本期精选文章的特色文章，第 1949 页。
