Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, Variants, or PubMed publications.

Have questions, comments, or suggestions? - Let us know!

Email us at : ckbsupport@genomenon.com

Ref Type
PMID (26992226)
Authors Patani H, Bunney TD, Thiyagarajan N, Norman RA, Ogg D, Breed J, Ashford P, Potterton A, Edwards M, Williams SV, Thomson GS, Pang CS, Knowles MA, Breeze AL, Orengo C, Phillips C, Katan M
Title Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use.
Journal Vol Issue Date Pages Journal Short Title
Oncotarget 2016 Mar 16 24252-68 Oncotarget
URL
Abstract Text 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.

Filtering

  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
  • Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

  • Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR3 A500T missense no effect FGFR3 A500T lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). A500T demonstrates autophosphorylation and substrate phosphorylation similar to wild-type Fgfr3 in cell culture (PMID: 26992226).
FGFR3 C582F missense no effect FGFR3 C582F lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). C582F demonstrates autophosphorylation and substrate phosphorylation similar to wild-type Fgfr3 in cell culture (PMID: 26992226).
FGFR3 D617G missense loss of function - predicted FGFR3 D617G lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). D617G results in a loss of Fgfr3 activity in cell culture (PMID: 26992226), and therefore, is predicted to lead to a loss of Fgfr3 protein function.
FGFR3 D641G missense gain of function FGFR3 D641G lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). D641G results in increased Fgfr3 autophosphorylation and substrate phosphorylation in cell culture (PMID: 26992226).
FGFR3 D641N missense gain of function - predicted FGFR3 D641N lies within the TK-2 domain of the Fgfr3 protein (PMID: 19287463). D641N results in proliferation similar to wild-type Fgfr3 in a competition assay and transformation activity similar to wild-type Fgfr3 in cultured cells (PMID: 34272467), but increased Fgfr3 autophosphorylation and substrate phosphorylation in culture (PMID: 26992226), and therefore, is predicted to lead to a gain of Fgfr3 protein function.
FGFR3 D646Y missense no effect FGFR3 D646Y lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). D646Y demonstrates autophosphorylation and substrate phosphorylation similar to the level of wild-type Fgfr3 in cell culture (PMID: 26992226).
FGFR3 E466K missense no effect FGFR3 E466K lies within the cytoplasmic domain of the Fgfr3 protein (UniProt.org). E466K demonstrates Fgfr3 autophosphorylation and substrate phosphorylation similar to wild-type Fgfr3 in cell culture (PMID: 26992226).
FGFR3 E627D missense no effect FGFR3 E627D lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). E627D demonstrates autophosphorylation and substrate phosphorylation similar to wild-type Fgfr3 in cell culture (PMID: 26992226).
FGFR3 G637W missense loss of function - predicted FGFR3 G637W lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). G637W results in a loss of Fgfr3 kinase activity in cell culture (PMID: 26992226), and therefore, is predicted to lead to a loss of Fgfr3 protein function.
FGFR3 G697C missense no effect FGFR3 G697C lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). G697C results in proliferation similar to wild-type Fgfr3 in a competition assay (PMID: 34272467), demonstrates autophosphorylation and substrate phosphorylation similar to wild-type Fgfr3, and is not transforming in cell culture (PMID: 26992226, PMID: 34272467).
FGFR3 H643D missense no effect FGFR3 H643D lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). H643D demonstrates autophosphorylation and substrate phosphorylation similar to wild-type Fgfr3 in cell culture (PMID: 26992226).
FGFR3 I538F missense no effect FGFR3 I538F lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). I538F demonstrates autophosphorylation and substrate phosphorylation similar to wild-type Fgfr3 in cell culture (PMID: 26992226).
FGFR3 I538V missense gain of function - predicted FGFR3 I538V lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). I538V results in increased Fgfr3 autophosphorylation in cell culture (PMID: 26992226), and therefore, is predicted to lead to a gain of Fgfr3 protein function.
FGFR3 N540K missense gain of function FGFR3 N540K lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). N540K results in increased Fgfr3 autophosphorylation and substrate phosphorylation, and is transforming in cell culture (PMID: 26992226). Y
FGFR3 N540S missense gain of function - predicted FGFR3 N540S lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). N540S results in increased Fgfr3 autophosphorylation in cell culture (PMID: 26992226), and therefore, is predicted to lead to a gain of Fgfr3 protein function.
FGFR3 N653H missense no effect FGFR3 N653H lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). N653H demonstrates autophosphorylation and substrate phosphorylation similar to wild-type Fgfr3 in cell culture (PMID: 26992226).
FGFR3 P572A missense no effect FGFR3 P572A lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). P572A demonstrates autophosphorylation and substrate phosphorylation similar to wild-type Fgfr3 in cell culture (PMID: 26992226).
FGFR3 R669G missense gain of function FGFR3 R669G lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). R669G results in increased Fgfr3 autophosphorylation and substrate phosphorylation in cell culture (PMID: 26992226).
FGFR3 R669Q missense gain of function - predicted FGFR3 R669Q lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). R669Q results in increased Fgfr3 autophosphorylation in cell culture (PMID: 26992226), and therefore, is predicted to lead to a gain of Fgfr3 protein function.
FGFR3 V555M missense gain of function FGFR3 V555M lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). V555M results in increased Fgfr3 autophosphorylation and substrate phosphorylation in cell culture (PMID: 26992226), and is associated with resistance to Fgfr inhibitors in culture (PMID: 28034880). Y
FGFR3 V630M missense no effect FGFR3 V630M lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). V630M demonstrates autophosphorylation and substrate phosphorylation similar to wild-type Fgfr3 in cell culture (PMID: 26992226).
FGFR3 V677I missense no effect FGFR3 V677I lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). V677I demonstrates autophosphorylation and substrate phosphorylation similar to wild-type Fgfr3 in cell culture (PMID: 26992226).
FGFR3 Y647C missense gain of function - predicted FGFR3 Y647C lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). Y647C results in increased Fgfr3 autophosphorylation in cell culture (PMID: 26992226), and therefore, is predicted to lead to a gain of Fgfr3 protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 N540K Advanced Solid Tumor resistant Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 N540K were reistant to growth inhibition by AZD4547 in culture (PMID: 26992226). 26992226
FGFR3 K650E Advanced Solid Tumor sensitive Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, Balversa (erdafitinib) inhibited proliferation of transformed cells expressing FGFR3 K650E in culture (PMID: 26992226). 26992226
FGFR3 K650E Advanced Solid Tumor decreased response Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 K650E demonstrated reduced sensitivity to growth inhibition by AZD4547 in culture (PMID: 26992226). 26992226
FGFR3 N540K Advanced Solid Tumor sensitive Erdafitinib Preclinical - Cell culture Actionable In a preclinicl study, Balversa (erdafitinib) inhibited proliferation of transformed cells expressing FGFR3 N540K in culture (PMID: 26992226). 26992226