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Ref Type Journal Article
PMID (27550940)
Authors Delpuech O, Rooney C, Mooney L, Baker D, Shaw R, Dymond M, Wang D, Zhang P, Cross S, Veldman-Jones M, Wilson J, Davies BR, Dry JR, Kilgour E, Smith PD
Title Identification of Pharmacodynamic Transcript Biomarkers in Response to FGFR Inhibition by AZD4547.
Journal Molecular cancer therapeutics
Vol 15
Issue 11
Date 2016 Nov
URL
Abstract Text The challenge of developing effective pharmacodynamic biomarkers for preclinical and clinical testing of FGFR signaling inhibition is significant. Assays that rely on the measurement of phospho-protein epitopes can be limited by the availability of effective antibody detection reagents. Transcript profiling enables accurate quantification of many biomarkers and provides a broader representation of pathway modulation. To identify dynamic transcript biomarkers of FGFR signaling inhibition by AZD4547, a potent inhibitor of FGF receptors 1, 2, and 3, a gene expression profiling study was performed in FGFR2-amplified, drug-sensitive tumor cell lines. Consistent with known signaling pathways activated by FGFR, we identified transcript biomarkers downstream of the RAS-MAPK and PI3K/AKT pathways. Using different tumor cell lines in vitro and xenografts in vivo, we confirmed that some of these transcript biomarkers (DUSP6, ETV5, YPEL2) were modulated downstream of oncogenic FGFR1, 2, 3, whereas others showed selective modulation only by FGFR2 signaling (EGR1). These transcripts showed consistent time-dependent modulation, corresponding to the plasma exposure of AZD4547 and inhibition of phosphorylation of the downstream signaling molecules FRS2 or ERK. Combination of FGFR and AKT inhibition in an FGFR2-mutated endometrial cancer xenograft model enhanced modulation of transcript biomarkers from the PI3K/AKT pathway and tumor growth inhibition. These biomarkers were detected on the clinically validated nanoString platform. Taken together, these data identified novel dynamic transcript biomarkers of FGFR inhibition that were validated in a number of in vivo models, and which are more robustly modulated by FGFR inhibition than some conventional downstream signaling protein biomarkers. Mol Cancer Ther; 15(11); 2802-13. ©2016 AACR.

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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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 rearrange lung small cell carcinoma sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited survival of small cell lung cancer cells harboring FGFR1 translocation in culture (PMID: 27550940). 27550940
FGFR2 amp endometrial cancer sensitive AZD4547 Preclinical - Cell line xenograft Actionable In a preclinical study, AZD4547 inhibited survival of FGFR2 amplified endometrial cancer cells in cell line xenograft models (PMID: 27550940). 27550940
FGFR3 fusion urinary bladder cancer sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited survival of bladder cancer cells harboring FGFR3 fusion in culture (PMID: 27550940). 27550940
FGFR2 amp breast cancer sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited survival of FGFR2 amplified breast cancer cells in culture (PMID: 27550940). 27550940
FGFR3 mutant urinary bladder cancer sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited survival of bladder cancer cells harboring FGFR3 mutation in culture (PMID: 27550940). 27550940
FGFR3 rearrange myeloid neoplasm sensitive AZD4547 Preclinical - Cell line xenograft Actionable In a preclinical study, AZD4547 inhibited survival of myeloma cells harboring FGFR3 translocation in culture and in cell line xenograft models (PMID: 27550940). 27550940
FGFR1 rearrange leukemia sensitive AZD4547 Preclinical - Cell line xenograft Actionable In a preclinical study, AZD4547 inhibited survival of leukemia cells harboring FGFR1 translocation in culture and in cell line xenograft models (PMID: 27550940). 27550940
FGFR2 amp colon cancer sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited survival of FGFR2 amplified colon cancer cells in culture (PMID: 27550940). 27550940