Analysis of fibroblast growth factor receptor 3 G697C mutation in oral squamous cell carcinomas

Aubertin, Johannes; Tourpin, Sophie; Janot, F.; Ahomadegbe, Jean‐Charles; Radvanyi, François

doi:10.1002/ijc.22285

Cited by 13 publications

(8 citation statements)

References 14 publications

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“…It is possible that the activating potential of this mutation could be context dependent and involve interaction with another component(s) present in this type of epithelial cells. Interestingly, another study examining a comparable number of OSCC cases from a different population failed to detect FGFR3 G697C, arguing that this mutation is unlikely to be common even in this cancer type [ 51 ]. It is also conceivable that the occurrence of this mutation in a specific population could be unrelated to FGFR activation and involvement in OSCC.…”

Section: Discussionmentioning

confidence: 99%

Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use

et al. 2016

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Frequent genetic alterations discovered in FGFRs and evidence implicating some as drivers in diverse tumors has been accompanied by rapid progress in targeting FGFRs for anticancer treatments. Wider assessment of the impact of genetic changes on the activation state and drug responses is needed to better link the genomic data and treatment options. We here apply a direct comparative and comprehensive analysis of FGFR3 kinase domain variants representing the diversity of point-mutations reported in this domain. We reinforce the importance of N540K and K650E and establish that not all highly activating mutations (for example R669G) occur at high-frequency and conversely, that some “hotspots” may not be linked to activation. Further structural characterization consolidates a mechanistic view of FGFR kinase activation and extends insights into drug binding. Importantly, using several inhibitors of particular clinical interest (AZD4547, BGJ-398, TKI258, JNJ42756493 and AP24534), we find that some activating mutations (including different replacements of the same residue) result in distinct changes in their efficacy. Considering that there is no approved inhibitor for anticancer treatments based on FGFR-targeting, this information will be immediately translatable to ongoing clinical trials.

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Section: Discussionmentioning

confidence: 99%

Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use

et al. 2016

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“…Regarding a role for somatic gain-of-function mutations in specific FGFRs, a published report revealed frequent (62%) mutation of FGFR3 (G697C) in primary HNSCC derived from Japanese patients (42). However, an independent screening of a French head and neck cancer patient population revealed no evidence for this FGFR3 mutation (43). Also, the COSMIC database reveals no identified FGFR3 mutations in any of the 22 HNSCC cell lines that were sequenced.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor Receptors Are Components of Autocrine Signaling Networks in Head and Neck Squamous Cell Carcinoma Cells

Marshall

Hinz

Kono

et al. 2011

Clinical Cancer Research

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Purpose We previously reported that a fibroblast growth factor (FGF) receptor (FGFR) signaling pathway drives growth of lung cancer cell lines of squamous and large cell histologies. Herein, we explored FGFR dependency in cell lines derived from the tobacco-related malignancy, head and neck squamous cell carcinoma (HNSCC). Experimental Design FGF and FGFR mRNA and protein expression was assessed in nine HNSCC cell lines. Dependence on secreted FGF2 for cell growth was tested with FP-1039, an FGFR1-Fc fusion protein. FGFR and EGFR-dependence was defined by sensitivity to multiple inhibitors selective for FGFRs or EGFR. Results FGF2 was expressed in eight of the nine HNSCC cell lines examined. Also, FGFR2 and FGFR3 were frequently expressed while only two lines expressed FGFR1. FP-1039 inhibited growth of HNSCC cell lines expressing FGF2, identifying FGF2 as an autocrine growth factor. FGFR inhibitors selectively reduced in vitro growth and ERK signaling in three HNSCC cell lines while three distinct lines exhibited responsiveness to both EGFR and FGFR inhibitors. Combinations of these drugs yielded additive growth inhibition. Finally, three cell lines were highly sensitive to EGFR TKIs with no contribution from FGFR pathways. Conclusions FGFR signaling was dominant or co-dominant with EGFR in six HNSCC lines while three lines exhibited little or no role for FGFRs and were highly EGFR-dependent. Thus, the HNSCC cell lines can be divided into subsets defined by sensitivity to EGFR and FGFR-specific TKIs. FGFR inhibitors may represent novel therapeutics to deploy alone or in combination with EGFR inhibitors in HNSCC.

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“…9 Subsequent follow-up studies on oral SCC from other countries failed to find the G697C mutation, indicating that this mutation might be a geographically restricted variant not widely associated with the pathogenesis of this tumor. 23 Given the high mutation rate in head and neck squamous cell carcinoma, it is likely that this particular FGFR3 mutation is simply a passenger mutation, or perhaps can only act in the context of additional driver mutations.…”

Section: Fgfr3 Mutations R248c and S249c But Not G697c Activate Mapmentioning

confidence: 99%

Activating FGFR3 mutations cause mild hyperplasia in human skin, but are insufficient to drive benign or malignant skin tumors

Duperret

McNeal

et al. 2014

Cell Cycle

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Analysis of fibroblast growth factor receptor 3 G697C mutation in oral squamous cell carcinomas

Cited by 13 publications

References 14 publications

Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use

Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use

Fibroblast Growth Factor Receptors Are Components of Autocrine Signaling Networks in Head and Neck Squamous Cell Carcinoma Cells

Activating FGFR3 mutations cause mild hyperplasia in human skin, but are insufficient to drive benign or malignant skin tumors

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