Department of Therapeutic Radiology, Yale University School of Medicine. New Haven, Connecticut.
Department of Medical Oncology, West German Cancer Center, University of Duisburg-Essen, Essen, Germany.
Cancer Res. 2020 Nov 1;80(21):4655-4667. doi: 10.1158/0008-5472.CAN-20-1192. Epub 2020 Sep 1.
Development of resistance remains the key obstacle to the clinical efficacy of EGFR tyrosine kinase inhibitors (TKI). Hypoxia is a key microenvironmental stress in solid tumors associated with acquired resistance to conventional therapy. Consistent with our previous studies, we show here that long-term, moderate hypoxia promotes resistance to the EGFR TKI osimertinib (AZD9291) in the non-small cell lung cancer (NSCLC) cell line H1975, which harbors two EGFR mutations including T790M. Hypoxia-induced resistance was associated with development of epithelial-mesenchymal transition (EMT) coordinated by increased expression of ZEB-1, an EMT activator. Hypoxia induced increased fibroblast growth factor receptor 1 (FGFR1) expression in NSCLC cell lines H1975, HCC827, and YLR086, and knockdown of FGFR1 attenuated hypoxia-induced EGFR TKI resistance in each line. Upregulated expression of FGFR1 by hypoxia was mediated through the MAPK pathway and attenuated induction of the proapoptotic factor BIM. Consistent with this, inhibition of FGFR1 function by the selective small-molecule inhibitor BGJ398 enhanced EGFR TKI sensitivity and promoted upregulation of BIM levels. Furthermore, inhibition of MEK activity by trametinib showed similar effects. In tumor xenografts in mice, treatment with either BGJ398 or trametinib enhanced response to AZD9291 and improved survival. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through increased expression of FGFR1. The combination of EGFR TKI and FGFR1 or MEK inhibitors may offer an attractive therapeutic strategy for NSCLC. SIGNIFICANCE: Hypoxia-induced resistance to EGFR TKI is driven by overexpression of FGFR1 to sustain ERK signaling, where a subsequent combination of EGFR TKI with FGFR1 inhibitors or MEK inhibitors reverses this resistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/21/4655/F1.large.jpg.
耐药性的发展仍然是 EGFR 酪氨酸激酶抑制剂（TKI）临床疗效的关键障碍。缺氧是实体瘤中与传统治疗获得性耐药相关的关键微环境应激。与我们之前的研究一致，我们在这里表明，长期中度缺氧会促进非小细胞肺癌（NSCLC）细胞系 H1975 对 EGFR TKI 奥希替尼（AZD9291）的耐药性，该细胞系携带包括 T790M 在内的两种 EGFR 突变。缺氧诱导的耐药性与 EMT 的发展有关，由 EMT 激活物 ZEB-1 的表达增加协调。缺氧诱导 NSCLC 细胞系 H1975、HCC827 和 YLR086 中 FGFR1 的表达增加，并且 FGFR1 的敲低减弱了每条线中缺氧诱导的 EGFR TKI 耐药性。缺氧通过 MAPK 途径介导 FGFR1 的上调，并减弱了促凋亡因子 BIM 的诱导。与之一致，选择性小分子抑制剂 BGJ398 抑制 FGFR1 功能增强了 EGFR TKI 的敏感性并促进了 BIM 水平的上调。此外，MEK 抑制剂 trametinib 的抑制作用也显示出类似的效果。在小鼠肿瘤异种移植中，BGJ398 或 trametinib 的治疗增强了对 AZD9291 的反应并改善了生存。这些结果表明，缺氧通过增加 FGFR1 的表达成为获得性 EGFR TKI 耐药的驱动力。EGFR TKI 和 FGFR1 或 MEK 抑制剂的联合治疗可能为 NSCLC 提供一种有吸引力的治疗策略。意义：缺氧诱导的 EGFR TKI 耐药性是由 FGFR1 的过表达驱动的，以维持 ERK 信号，随后将 EGFR TKI 与 FGFR1 抑制剂或 MEK 抑制剂联合使用可逆转这种耐药性。
