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

Bogatyrova, Olga ; Mattsson, Johanna S.M. ; Ross, Edith M. ; Sanderson, Michael P. ; Backman, Max ; Botling, Johan ; Brunnström, Hans LU orcid ; Kurppa, Pinja ; La Fleur, Linnéa and Strell, Carina , et al. (2021) In European Journal of Cancer 151. p.136-149
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cancer immunity, FGFR1, miRNA, Non-small cell lung cancer, Promoter methylation
in
European Journal of Cancer
volume
151
pages
14 pages
publisher
Elsevier
external identifiers
  • scopus:85105433182
  • pmid:33984662
ISSN
0959-8049
DOI
10.1016/j.ejca.2021.04.005
language
English
LU publication?
yes
id
beff5db8-3dcb-479f-b0a6-1f01c9c94951
date added to LUP
2021-05-27 16:19:13
date last changed
2022-09-24 22:06:53
@article{beff5db8-3dcb-479f-b0a6-1f01c9c94951,
  abstract     = {{<p>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.</p>}},
  author       = {{Bogatyrova, Olga and Mattsson, Johanna S.M. and Ross, Edith M. and Sanderson, Michael P. and Backman, Max and Botling, Johan and Brunnström, Hans and Kurppa, Pinja and La Fleur, Linnéa and Strell, Carina and Wilm, Claudia and Zimmermann, Astrid and Esdar, Christina and Micke, Patrick}},
  issn         = {{0959-8049}},
  keywords     = {{Cancer immunity; FGFR1; miRNA; Non-small cell lung cancer; Promoter methylation}},
  language     = {{eng}},
  pages        = {{136--149}},
  publisher    = {{Elsevier}},
  series       = {{European Journal of Cancer}},
  title        = {{FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response}},
  url          = {{http://dx.doi.org/10.1016/j.ejca.2021.04.005}},
  doi          = {{10.1016/j.ejca.2021.04.005}},
  volume       = {{151}},
  year         = {{2021}},
}