1Department of Translational Genomics, University of Cologne; 2Max-Planck-Institute for Neurological Research; Institutes of 3Pathology and 4Virology, University of Cologne;5Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne; 6Blackfield AG, Cologne; 7Technical University Dortmund, Dortmund, Germany; 8Medical Oncology and 9Institute of Pathology, Cantonal Hospital, Luzern; 10Novartis Pharma AG, Basel, Switzerland; and 11Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, India.
Cancer Discov. 2014 Feb;4(2):246-57. doi: 10.1158/2159-8290.CD-13-0323. Epub 2013 Dec 3.
The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplified in squamous cell lung cancer. However, it is currently unknown which of the 8p12-amplified tumors are also sensitive to fibroblast growth factor receptor (FGFR) inhibition. We found that, in contrast with other recurrent amplifications, the 8p12 region included multiple centers of amplification, suggesting marked genomic heterogeneity. FGFR1-amplified tumor cells were dependent on FGFR ligands in vitro and in vivo. Furthermore, ectopic expression of FGFR1 was oncogenic, which was enhanced by expression of MYC. We found that MYC was coexpressed in 40% of FGFR1-amplified tumors. Tumor cells coexpressing MYC were more sensitive to FGFR inhibition, suggesting that patients with FGFR1-amplified and MYC-overexpressing tumors may benefit from FGFR inhibitor therapy. Thus, both cell-autonomous and non-cell-autonomous mechanisms of transformation modulate FGFR dependency in FGFR1-amplified lung cancer, which may have implications for patient selection for treatment with FGFR inhibitors.
Amplification of FGFR1 is one of the most frequent candidate targets in lung cancer. Here, we show that multiple factors affect the tumorigenic potential of FGFR1, thus providing clinical hypotheses for refinement of patient selection.
8p12 基因座（包含 FGFR1 酪氨酸激酶基因）在鳞状细胞肺癌中经常扩增。然而，目前尚不清楚哪些 8p12 扩增的肿瘤也对成纤维细胞生长因子受体（FGFR）抑制敏感。我们发现，与其他反复扩增不同，8p12 区域包含多个扩增中心，表明存在明显的基因组异质性。体外和体内实验表明，FGFR1 扩增的肿瘤细胞依赖 FGFR 配体。此外，FGFR1 的异位表达具有致癌性，而 MYC 的表达增强了其致癌性。我们发现，40%的 FGFR1 扩增肿瘤中共同表达 MYC。共表达 MYC 的肿瘤细胞对 FGFR 抑制更敏感，这表明 FGFR1 扩增和 MYC 过表达的肿瘤患者可能受益于 FGFR 抑制剂治疗。因此，细胞自主和非细胞自主的转化机制都调节了 FGFR1 扩增的肺癌对 FGFR 的依赖性，这可能对选择接受 FGFR 抑制剂治疗的患者具有重要意义。
FGFR1 扩增是肺癌中最常见的候选靶点之一。在这里，我们表明，多个因素影响 FGFR1 的肿瘤发生潜力，从而为完善患者选择提供了临床假说。
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