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Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma
- 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.
- Subjects :
- 0301 basic medicine
endocrine system
Lung Neoplasms
Phases of clinical research
Quinolones
03 medical and health sciences
0302 clinical medicine
Gene expression
Exome Sequencing
medicine
Humans
Lung cancer
Exome sequencing
Clinical Trials as Topic
business.industry
FGF19
Hematology
medicine.disease
Receptors, Fibroblast Growth Factor
Gene expression profiling
030104 developmental biology
Oncology
Tumor progression
030220 oncology & carcinogenesis
Mutation
Cancer research
Carcinoma, Squamous Cell
Biomarker (medicine)
Benzimidazoles
business
hormones, hormone substitutes, and hormone antagonists
Biomarkers
Signal Transduction
Subjects
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