Document Detail


Tumour cell responses to new fibroblast growth factor receptor tyrosine kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of acquired resistance.
MedLine Citation:
PMID:  22869148     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Fibroblast growth factor receptors (FGFRs) can act as driving oncoproteins in certain cancers, making them attractive drug targets. Here we have characterized tumour cell responses to two new inhibitors of FGFR1-3, AZ12908010 and the clinical candidate AZD4547, making comparisons with the well-characterized FGFR inhibitor PD173074. In a panel of 16 human tumour cell lines, the anti-proliferative activity of AZ12908010 or AZD4547 was strongly linked to the presence of deregulated FGFR signalling, indicating that addiction to deregulated FGFRs provides a therapeutic opportunity for selective intervention. Acquired resistance to targeted tyrosine kinase inhibitors is a growing problem in the clinic but has not yet been explored for FGFR inhibitors. To assess how FGFR-dependent tumour cells adapt to long-term FGFR inhibition, we generated a derivative of the KMS-11 myeloma cell line (FGFR(Y373C)) with acquired resistance to AZ12908010 (KMS-11R cells). Basal phosphorylated FGFR and FGFR-dependent downstream signalling were constitutively elevated and refractory to drug in KMS-11R cells. Sequencing of FGFR3 in KMS-11R cells revealed the presence of a heterozygous mutation at the gatekeeper residue, encoding FGFR3(V555M); consistent with this, KMS-11R cells were cross-resistant to AZD4547 and PD173074. These results define the selectivity and efficacy of two new FGFR inhibitors and identify a secondary gatekeeper mutation as a mechanism of acquired resistance to FGFR inhibitors that should be anticipated as clinical evaluation proceeds.
Authors:
V Chell; K Balmanno; A S Little; M Wilson; S Andrews; L Blockley; M Hampson; P R Gavine; S J Cook
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-08-06
Journal Detail:
Title:  Oncogene     Volume:  32     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-06-20     Completed Date:  2013-08-27     Revised Date:  2013-09-18    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  3059-70     Citation Subset:  IM    
Affiliation:
Signalling Laboratory, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Benzamides / pharmacology
Breast Neoplasms / drug therapy
Cell Line, Tumor
Drug Resistance, Neoplasm / genetics
Female
Humans
Multiple Myeloma / drug therapy,  genetics
Mutation
Neoplasms / drug therapy*
Piperazines / pharmacology
Pyrazoles / pharmacology
Pyrimidines / pharmacology
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*,  drug effects
Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors,  metabolism
Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors,  metabolism
Receptor, Fibroblast Growth Factor, Type 3 / antagonists & inhibitors,  genetics*
Receptors, Fibroblast Growth Factor / antagonists & inhibitors*,  metabolism
Signal Transduction / drug effects
Stomach Neoplasms / drug therapy
Urinary Bladder Neoplasms / drug therapy
Grant Support
ID/Acronym/Agency:
//Biotechnology and Biological Sciences Research Council
Chemical
Reg. No./Substance:
0/AZD4547; 0/Antineoplastic Agents; 0/Benzamides; 0/PD 173074; 0/Piperazines; 0/Pyrazoles; 0/Pyrimidines; 0/Receptors, Fibroblast Growth Factor; EC 2.7.10.1/FGFR1 protein, human; EC 2.7.10.1/FGFR2 protein, human; EC 2.7.10.1/FGFR3 protein, human; EC 2.7.10.1/Receptor Protein-Tyrosine Kinases; EC 2.7.10.1/Receptor, Fibroblast Growth Factor, Type 1; EC 2.7.10.1/Receptor, Fibroblast Growth Factor, Type 2; EC 2.7.10.1/Receptor, Fibroblast Growth Factor, Type 3

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