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Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma

Authors :
Hye Ryun Kim
Kyoung Ho Pyo
H.N. Kang
J.Y. Han
Hyo Sup Shim
Eun Young Kim
D.J. Kim
Byoung Chul Cho
Myung-Ju Ahn
S.-M. Kim
Hyun A. Youn
Jinna Kim
Min Hee Hong
Mi Ran Yun
Chang Young Lee
Jin Gu Lee
Tae Min Kim
Hwan Kim
Soonmyung Paik
H.J. Park
Source :
Annals of oncology : official journal of the European Society for Medical Oncology. 28(6)
Publication Year :
2017

Abstract

Background We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC). Methods The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected toin vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling. Results The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations ofFGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib. Conclusions FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.

Details

ISSN :
15698041
Volume :
28
Issue :
6
Database :
OpenAIRE
Journal :
Annals of oncology : official journal of the European Society for Medical Oncology
Accession number :
edsair.doi.dedup.....f201e7c11c6fc6f9df95fafdcdef9146