Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.
Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.
Mol Cancer Ther. 2020 Jun;19(6):1255-1265. doi: 10.1158/1535-7163.MCT-19-0931. Epub 2020 May 5.
FGFRs are commonly altered in non-small cell lung cancer (NSCLC). FGFRs activate multiple pathways including RAS/RAF/MAPK, PI3K/AKT, and STAT, which may play a role in the cellular response to radiation. We investigated the effects of combining the selective FGFR 1-3 tyrosine kinase inhibitor AZD4547 with radiation in cell line and xenograft models of NSCLC. NSCLC cell lines were assessed with proliferation, clonogenic survival, apoptosis, autophagy, cell cycle, and DNA damage signaling and repair assays. xenografts and IHC were used to confirm results. NSCLC cell lines demonstrated varying degrees of FGFR protein and mRNA expression. clonogenic survival assays showed radiosensitization with AZD4547 in two NSCLC cell lines. In these two cell lines, an increase in apoptosis and autophagy was observed with combined radiation and AZD4547. The addition of AZD4547 to radiation did not significantly affect γH2AX foci formation. Enhanced xenograft tumor growth delay was observed with the combination of radiation and AZD4547 compared with radiation or drug alone. IHC results revealed inhibition of pMAPK and pS6 and demonstrated an increase in apoptosis in the radiation plus AZD4547 group. This study demonstrates that FGFR inhibition by AZD4547 enhances the response of radiation in FGFR-expressing NSCLC and model systems. These results support further investigation of combining FGFR inhibition with radiation as a clinical therapeutic strategy.
成纤维细胞生长因子受体（FGFRs）在非小细胞肺癌（NSCLC）中常发生改变。FGFR 可激活多条信号通路，包括 RAS/RAF/MAPK、PI3K/AKT 和 STAT，这些信号通路可能在细胞对辐射的反应中发挥作用。我们研究了选择性 FGFR1-3 酪氨酸激酶抑制剂 AZD4547 与放疗联合应用于 NSCLC 细胞系和异种移植模型中的效果。我们用增殖、集落形成存活、细胞凋亡、自噬、细胞周期和 DNA 损伤信号和修复检测评估 NSCLC 细胞系。使用异种移植和免疫组化（IHC）来验证结果。NSCLC 细胞系表现出不同程度的 FGFR 蛋白和 mRNA 表达。集落形成存活检测显示，在两种 NSCLC 细胞系中，AZD4547 可增强放疗的放射敏感性。在这两种细胞系中，联合放疗和 AZD4547 可观察到细胞凋亡和自噬增加。与单独放疗或药物相比，AZD4547 联合放疗并未显著影响 γH2AX 焦点形成。与单独放疗或药物相比，联合放疗和 AZD4547 可显著延缓肿瘤生长。免疫组化结果显示，pMAPK 和 pS6 受到抑制，并且在放疗加 AZD4547 组中观察到细胞凋亡增加。本研究表明，AZD4547 抑制 FGFR 可增强 FGFR 表达的 NSCLC 模型系统对放疗的反应。这些结果支持进一步研究将 FGFR 抑制与放疗相结合作为一种临床治疗策略。
