文章：

Tasurgratinib作为一种口服可用的FGFR1-3抑制剂对ER+/HER2-乳腺癌临床前模型中CDK4/6抑制剂和内分泌治疗耐药性的影响

Effect of Tasurgratinib as an Orally Available FGFR1–3 Inhibitor on Resistance to a CDK4/6 Inhibitor and Endocrine Therapy in ER+/HER2−Breast Cancer Preclinical Models

原文发布日期：24 March 2025

DOI: 10.3390/cancers17071084

类型: Article

开放获取: 是

英文摘要：

Background: Fibroblast growth factor (FGF) signaling plays a crucial role in several cellular functions in cancer cells. Tasurgratinib, formerly known as E7090, is an orally available FGF receptor (FGFR)1–3 selective inhibitor. Here, we present the effects of tasurgratinib on the resistance to CDK4/6 inhibitors and endocrine therapy (ET) in a preclinical model. Methods: Estrogen receptor (ER)+breast cancer (BC) patient-derived xenograft (PDX) models harboringESR1wild-type orESR1mutation were used as animal models. An in vitro cell proliferation assay of ER+BC cell lines treated with fulvestrant or palbociclib + fulvestrant was conducted in the presence of FGF2 and FGF10, with or without tasurgratinib. Results: Among five ER+BC PDX models, OD-BRE-0438 and OD-BRE-0704 showed higher sensitivities to tasurgratinib with prior palbociclib + fulvestrant than without it. In these models, palbociclib + fulvestrant treatment upregulated the expression of severalFGFligand mRNAs. In vitro, FGF2 and FGF10 decreased the sensitivity to both fulvestrant and palbociclib + fulvestrant, which was restored by co-treatment with tasurgratinib. Consistently, fulvestrant + tasurgratinib and elacestrant + tasurgratinib showed antitumor activity in ER+BC PDX models harboringESR1wild-type andESR1mutation, respectively. In these models, fulvestrant or elacestrant upregulated the expression of severalFGFligand mRNAs. Conclusions: FGF signaling plays a role in resistance to CDK4/6 inhibitors and ET in ER+BC. Tasurgratinib has the potential to exhibit significant antitumor activity in combination with ET against ER+BC via FGF signaling inhibition. These findings indicate the therapeutic potential of tasurgratinib in treating ER+BC.

摘要翻译： 

背景：成纤维细胞生长因子（FGF）信号通路在癌细胞的多种细胞功能中发挥关键作用。Tasurgratinib（曾用名E7090）是一种口服有效的FGF受体（FGFR）1-3选择性抑制剂。本研究在临床前模型中探讨了tasurgratinib对CDK4/6抑制剂及内分泌治疗（ET）耐药性的影响。方法：采用携带ESR1野生型或ESR1突变的雌激素受体（ER）阳性乳腺癌（BC）患者来源异种移植（PDX）模型作为动物模型。在FGF2和FGF10存在条件下，对ER阳性BC细胞系进行氟维司群或帕博西尼+氟维司群处理的体外细胞增殖实验，并设置联合或不联合tasurgratinib的实验组。结果：在五种ER阳性BC PDX模型中，OD-BRE-0438和OD-BRE-0704模型在预先接受帕博西尼+氟维司群治疗后，对tasurgratinib的敏感性显著高于未接受该预处理组。在这些模型中，帕博西尼+氟维司群治疗上调了多种FGF配体mRNA的表达。体外实验表明，FGF2和FGF10会降低细胞对氟维司群及帕博西尼+氟维司群的敏感性，而联合使用tasurgratinib可恢复这种敏感性。一致性地，在携带ESR1野生型和ESR1突变的ER阳性BC PDX模型中，氟维司群+tasurgratinib与elacestrant+tasurgratinib分别显示出抗肿瘤活性。在这些模型中，氟维司群或elacestrant均上调了多种FGF配体mRNA的表达。结论：FGF信号通路参与ER阳性BC对CDK4/6抑制剂及ET的耐药过程。Tasurgratinib通过抑制FGF信号通路，与ET联用可能对ER阳性BC产生显著抗肿瘤活性。这些发现揭示了tasurgratinib在治疗ER阳性BC方面的治疗潜力。

原文链接：

Effect of Tasurgratinib as an Orally Available FGFR1–3 Inhibitor on Resistance to a CDK4/6 Inhibitor and Endocrine Therapy in ER+/HER2−Breast Cancer Preclinical Models