Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	15	11	2016 Nov	2802-2813	Mol Cancer Ther

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
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
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
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
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
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
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
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