Introduction: There is substantial evidence for the oncogenic effects of fibroblast growth factor receptor 1 (FGFR1) in many types of cancer, including lung cancer, but the role of this receptor has not been addressed specifically in lung adenocarcinoma. Methods: We performed FGFR1 and EGFR overexpression and co‐overexpression assays in adenocarcinoma and in inmortalized lung cell lines, and we also carried out surrogate and interaction assays. We performed monotherapy and combination EGFR/FGFR inhibitor sensitivity assays in vitro and in vivo in cell line– and patient‐derived xenografts. We determined FGFR1 mRNA expression in a cohort of patients with anti–EGFR therapy–treated adenocarcinoma. Results: We have reported a cooperative interaction between FGFR1 and EGFR in this context, resulting in increased EGFR activation and oncogenic signaling. We have provided in vitro and in vivo evidence indicating that FGFR1 expression increases tumorigenicity in cells with high EGFR activation in EGFR‐mutated and EGFR wild‐type models. At the clinical level, we have shown that high FGFR1 expression levels predict higher resistance to erlotinib or gefitinib in a cohort of patients with tyrosine kinase inhibitor–treated EGFR‐mutated and EGFR wild‐type lung adenocarcinoma. Dual EGFR and FGFR inhibition in FGFR1‐overexpressing, EGFR‐activated models shows synergistic effects on tumor growth in vitro and in cell line– and patient‐derived xenografts, suggesting that patients with tumors bearing these characteristics may benefit from combined EGFR/FGFR inhibition. Conclusion: These results support the extended the use of EGFR inhibitors beyond monotherapy in the EGFR‐mutated adenocarcinoma setting in combination with FGFR inhibitors for selected patients with increased FGFR1 overexpression and EGFR activation.

中文翻译：

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FGFR1在肺癌肿瘤发生中与EGFR合作，它们的联合抑制显示出更好的疗效

简介：有大量证据表明成纤维细胞生长因子受体 1 (FGFR1) 在包括肺癌在内的多种癌症中具有致癌作用，但该受体在肺腺癌中的作用尚未明确。方法：我们在腺癌和永生化肺细胞系中进行了 FGFR1 和 EGFR 过表达和共过表达测定，我们还进行了替代和相互作用测定。我们在细胞系和患者来源的异种移植物中进行了体外和体内单一疗法和联合 EGFR/FGFR 抑制剂敏感性测定。我们确定了一组接受抗 EGFR 治疗的腺癌患者的 FGFR1 mRNA 表达。结果：我们报告了 FGFR1 和 EGFR 在这种情况下的合作相互作用，导致 EGFR 激活和致癌信号增加。我们提供的体外和体内证据表明，在 EGFR 突变和 EGFR 野生型模型中，FGFR1 表达会增加 EGFR 高激活细胞的致瘤性。在临床水平上，我们已经表明，在酪氨酸激酶抑制剂治疗的 EGFR 突变和 EGFR 野生型肺腺癌患者队列中，高 FGFR1 表达水平预测对厄洛替尼或吉非替尼的更高耐药性。在 FGFR1 过表达、EGFR 激活模型中双重 EGFR 和 FGFR 抑制显示对体外和细胞系和患者来源的异种移植物中肿瘤生长的协同作用，表明具有这些特征的肿瘤患者可能受益于联合 EGFR/FGFR 抑制。结论：