FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response

被引:30
作者
Bogatyrova, Olga [1 ]
Mattsson, Johanna S. M. [2 ]
Ross, Edith M. [3 ]
Sanderson, Michael P. [1 ]
Backman, Max [2 ]
Botling, Johan [2 ]
Brunnstrom, Hans [4 ]
Kurppa, Pinja [2 ]
La Fleur, Linnea [2 ]
Strell, Carina [2 ]
Wilm, Claudia [1 ]
Zimmermann, Astrid [1 ]
Esdar, Christina [1 ]
Micke, Patrick [2 ]
机构
[1] Merck KGaA, Translat Innovat Platform Oncol & Immunooncol, Darmstadt, Germany
[2] Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden
[3] Merck KGaA, Translat Med, Darmstadt, Germany
[4] Lund Univ, Skane Univ Hosp, Div Pathol, Lund, Sweden
关键词
FGFR1; Non-small cell lung cancer; Promoter methylation; miRNA; Cancer immunity; GROWTH-FACTOR RECEPTORS; PROGNOSTIC IMPACT; IMMUNE LANDSCAPE; TUMOR; EXPRESSION; THERAPY; PATHWAY; CHOLANGIOCARCINOMA; SENSITIVITY; DIAGNOSTICS;
D O I
10.1016/j.ejca.2021.04.005
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Amplification of fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) has been considered as an actionable drug target. However, pan-FGFR tyrosine kinase inhibitors did not demonstrate convincing clinical efficacy in FGFR1-amplified NSCLC patients. This study aimed to characterise the molecular context of FGFR1 expression and to define biomarkers predictive of FGFR1 inhibitor response. In this study, 635 NSCLC samples were characterised for FGFR1 protein expression by immunohistochemistry and copy number gain (CNG) by in situ hybridisation (n = 298) or DNA microarray (n = 189). FGFR1 gene expression (n = 369) and immune cell profiles (n = 309) were also examined. Furthermore, gene expression, methylation and microRNA data from The Cancer Genome Atlas (TCGA) were compared. A panel of FGFR1-amplified NSCLC patient-derived xenograft (PDX) models were tested for response to the selective FGFR1 antagonist M6123. A minority of patients demonstrated FGFR1 CNG (10.5%) or increased FGFR1 mRNA (8.7%) and protein expression (4.4%). FGFR1 CNG correlated weakly with FGFR1 gene and protein expression. Tumours overexpressing FGFR1 protein were typically devoid of driver alterations (e.g. EGFR, KRAS) and showed reduced infiltration of T-lymphocytes and lower PD-L1 expression. Promoter methylation and microRNA were identified as regulators of FGFR1 expression in NSCLC and other cancers. Finally, NSCLC PDX models demonstrating FGFR1 amplification and FGFR1 protein overexpression were sensitive to M6123. The unique molecular and immune features of tumours with high FGFR1 expression provide a rationale to stratify patients in future clinical trials of FGFR1 pathway-targeting agents. (C) 2021 The Author(s). Published by Elsevier Ltd.
引用
收藏
页码:136 / 149
页数:14
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