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 Sofia Margareta; Ross, Edith; Sanderson, Michael P.; Backman, Max; Botling, Johan; Brunnström, Hans; Kurppa, Pinja; Fleur, Linnéa La; Strell, Carina; Wilm, Claudia; Zimmermann, Astrid; Esdar, Christina; Micke, Patrick

doi:10.1016/j.ejca.2021.04.005

Cited by 31 publications

(26 citation statements)

References 65 publications

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“…Increased FGFR1 mRNA levels are frequently observed in Sq-NSCLC. Medium and high tumor FGFR1 mRNA expression was reported in 27-60% of patients with Sq-NSCLC (4,19,26), and 55 of 118 (47%) Sq-NSCLC tumors had FGFR1-3 mRNA overexpression (55,56).…”

Section: Fgfr Mrna/protein Overexpressionmentioning

confidence: 98%

Fibroblast Growth Factor Receptor 1-4 Genetic Aberrations as Clinically Relevant Biomarkers in Squamous Cell Lung Cancer

Moes-Sosnowska¹,

Chorostowska‐Wynimko²

2022

Front. Oncol.

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Fibroblast growth factor receptor (FGFR) inhibitors (FGFRis) are a potential therapeutic option for squamous non-small cell lung cancer (Sq-NSCLC). Because appropriate patient selection is needed for targeted therapy, molecular profiling is key to discovering candidate biomarker(s). Multiple FGFR aberrations are present in Sq-NSCLC tumors—alterations (mutations and fusions), amplification and mRNA/protein overexpression—but their predictive potential is unclear. Although FGFR1 amplification reliability was unsatisfactory, FGFR mRNA overexpression, mutations, and fusions are promising. However, currently their discriminatory power is insufficient, and the available clinical data are from small groups of Sq-NSCLC patients. Here, we focus on FGFR aberrations as predictive biomarkers for FGFR-targeting agents in Sq-NSCLC. Known and suggested molecular determinants of FGFRi resistance are also discussed.

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Section: Fgfr Mrna/protein Overexpressionmentioning

confidence: 98%

Fibroblast Growth Factor Receptor 1-4 Genetic Aberrations as Clinically Relevant Biomarkers in Squamous Cell Lung Cancer

Moes-Sosnowska¹,

Chorostowska‐Wynimko²

2022

Front. Oncol.

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“…FGFR1 is a cell-surface receptor for broblast growth factors that regulate embryonic development, cell proliferation, differentiation, and migration. Its ampli cation has been frequently reported in NSCLC [37]. Proto-oncogene LCK encodes lymphocyte-speci c protein tyrosine kinase LCK, an Src family tyrosine kinase, which plays an important role in TCR-linked signal transduction.…”

Section: Wm1 and Wm2 Modulesmentioning

confidence: 99%

Identification of upstream immunoregulators that target protein co-expression networks significantly associated with early-stage micropapillary/solid predominant lung adenocarcinomas

Nishimura

Nakamura

Fujii

et al. 2022

Preprint

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Micropapillary- and solid-predominant lung adenocarcinomas (MPA and SPA), high-risk subtypes with poor outcomes, remain their molecular profiles unclarified. This study aimed at identifying the disease-related protein networks associated with early-stage MPA and SPA. We assessed cancerous cells laser-microdissected from FFPE tissues of an MPA group (n = 3) and a SPA group (n = 5), referencing the lepidic predominant subtype group (LPA) (n = 4). We identified forty modules of protein co-expression networks by applying a weighted network correlation analysis to the quantitative proteome datasets. Upstream analysis was then applied to four modules significantly associated with MPA or SPA. The redox master regulator NFE2L2 was activated commonly in both MPA and SPA cases. The two MPA-significant modules suggested p53 inactivation by dual mechanisms. One involves NGFR (p75NTR) and another the highly expressed myoferlin (MYOF), potentially induced by the ASPSCR1-TFE3 oncoprotein. The two SPA-significant modules commonly predicted the highly inhibited LARP1, indicating oncogenic IRES-dependent translation. Moreover, together with our observation of the highly expressed immune checkpoint molecules HLA-G and IDO1, activated regulators of adaptive immune response and inhibition of LILRB2 implicated that early-stage SPA is already associated with anti-tumor immune tolerance. Our findings might help develop future therapeutic strategies.

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“…10 FGFR1 is part of a four-member family (FGFR1-4) of transmembrane receptors activated by 22 different FGF ligands. 11 FGFR dimerization and conformational changes eventually lead to the downstream activation of PI3K/Akt/mTOR pathway, mediating proliferation, migration, and survival of cancer cells. 12,13 Hence, we aimed to evaluate FGFR1 and phosphorylated Akt (p-Akt) protein expression in OL and TSCC, and FGFR1 gene amplification in TSCC.…”

Section: Introductionmentioning

confidence: 99%

“…FGFR1 is part of a four‐member family (FGFR1‐4) of transmembrane receptors activated by 22 different FGF ligands 11 . FGFR dimerization and conformational changes eventually lead to the downstream activation of PI3K/Akt/mTOR pathway, mediating proliferation, migration, and survival of cancer cells 12,13 .…”

Section: Introductionmentioning

confidence: 99%

FGFR1 is an important prognostic factor in oral leukoplakia and tongue squamous cell carcinoma

Mariz

Sá

Araujo

et al. 2023

J Oral Pathology Medicine

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Background Fibroblast growth factor receptor 1 is a potential prognostic factor for tongue squamous cell carcinoma and is associated with oral epithelial dysplasia grade in oral leukoplakia. Methods Thirty cases of tongue squamous cell carcinoma and 30 cases of oral leukoplakia were analyzed. Fibroblast growth factor receptor 1 and phosphorylated Akt protein expression were analyzed by immunohistochemistry and quantified using a digital algorithm. Fibroblast growth factor receptor 1 gene amplification was analyzed by fluorescent in situ hybridization in the tongue squamous cell carcinoma cases. Results Clinical appearance and dysplasia grade were correlated with oral leukoplakia malignant transformation. Oral leukoplakia cases presenting high fibroblast growth factor receptor 1 expression showed a higher risk of malignant transformation (p = 0.016, HR: 7.3, 95% CI: 1.4–37.4). Phosphorylated Akt showed faint to no expression in oral leukoplakia, which did not correlate with dysplasia grade or malignant transformation. High expression of fibroblast growth factor receptor 1 and phosohorylated Akt were associated with poor overall survival and disease‐free survival in tongue squamous cell carcinoma, although only fibroblast growth factor receptor 1 expression was significantly associated with poor overall survival (p = 0.024; HR: 4.9, 95% CI: 1.2–19.9). Cases presenting double fibroblast growth factor receptor 1/phosphorylated Akt overexpression (n = 8) showed markedly impaired overall survival (p = 0.020; HR: 6.4, 95% CI: 1.3–31.1) and disease‐free survival (p = 0.001, HR: 13.0, 95% CI: 3.0–55.7). Fibroblast growth factor receptor 1 amplification was observed in 16.6% of tongue squamous cell carcinoma cases, being correlated with vascular and neural invasion (p = 0.001 and 0.017, respectively), but not with fibroblast growth factor receptor 1 protein expression, overall survival, or disease‐free survival. Conclusion Fibroblast growth factor receptor 1 protein expression is an important prognostic factor in oral leukoplakia and tongue squamous cell carcinoma.

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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

Cited by 31 publications

References 65 publications

Fibroblast Growth Factor Receptor 1-4 Genetic Aberrations as Clinically Relevant Biomarkers in Squamous Cell Lung Cancer

Fibroblast Growth Factor Receptor 1-4 Genetic Aberrations as Clinically Relevant Biomarkers in Squamous Cell Lung Cancer

Identification of upstream immunoregulators that target protein co-expression networks significantly associated with early-stage micropapillary/solid predominant lung adenocarcinomas

FGFR1 is an important prognostic factor in oral leukoplakia and tongue squamous cell carcinoma

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