title: Identification of Pharmacodynamic Transcript Biomarkers in Response to FGFR Inhibition by AZD4547.
abstract: 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.
authors.affiliation: AstraZeneca Pharmaceutical, Oncology iMed, CRUK-CI, Li Ka Shing Centre, Cambridge, United Kingdom. oona.delpuech@astrazenca.com.
authors.forename: Oona
authors.initials: O
authors.lastname: Delpuech
authors.affiliation: AstraZeneca Pharmaceutical, Darwing Building, Cambridge, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Rooney
authors.affiliation: AstraZeneca Pharmaceutical, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Mooney
authors.affiliation: AstraZeneca Pharmaceutical, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Dawn
authors.initials: D
authors.lastname: Baker
authors.affiliation: AstraZeneca Pharmaceutical, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Shaw
authors.affiliation: AstraZeneca Pharmaceutical, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Dymond
authors.affiliation: AstraZeneca Pharmaceutical, Oncology iMed, CRUK-CI, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wang
authors.affiliation: AstraZeneca Pharmaceutical, Oncology iMed, CRUK-CI, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.affiliation: AstraZeneca Pharmaceutical, Riverside, Granta Park, Cambridge, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Cross
authors.affiliation: AstraZeneca Pharmaceutical, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Margaret
authors.initials: M
authors.lastname: Veldman-Jones
authors.affiliation: AstraZeneca Pharmaceutical, Oncology iMed, CRUK-CI, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Wilson
authors.affiliation: AstraZeneca Pharmaceutical, Oncology iMed, CRUK-CI, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
authors.affiliation: AstraZeneca Pharmaceutical, Gatehouse, Waltham, Massachusetts.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dry
authors.affiliation: AstraZeneca Pharmaceutical, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Elaine
authors.initials: E
authors.lastname: Kilgour
authors.affiliation: AstraZeneca Pharmaceutical, Oncology iMed, CRUK-CI, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smith
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D064593:Heterografts; D006801:Humans; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome
chemical_list: C572463:AZD4547; D000970:Antineoplastic Agents; D001549:Benzamides; D015415:Biomarkers; D010879:Piperazines; D011720:Pyrazoles; D017468:Receptors, Fibroblast Growth Factor