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

H. R. Kim, H. N. Kang, H. S. Shim, E. Y. Kim, J. Kim, D. J. Kim, J. G. Lee, C. Y. Lee, M. H. Hong, S. M. Kim, H. Kim, K. H. Pyo, M. R. Yun, H. J. Park, J. Y. Han, H. A. Youn, M. J. Ahn, S. Paik, T. M. Kim, B. C. Cho

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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 to in 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 of FGFR1-3 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 SHCmediated 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.

Original languageEnglish
Article numbermdx098
Pages (from-to)1250-1259
Number of pages10
JournalAnnals of Oncology
Volume28
Issue number6
DOIs
Publication statusPublished - 2017 Jun 1

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Squamous Cell Carcinoma
Heterografts
Biomarkers
Clinical Trials
Lung
Transcriptome
Neoplasms
4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
Cell Line
Encyclopedias
Exome
Gene Expression Profiling
Transcriptional Activation
Genes
Lung Neoplasms
Genome
Databases
Ligands

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology

Cite this

Kim, H. R. ; Kang, H. N. ; Shim, H. S. ; Kim, E. Y. ; Kim, J. ; Kim, D. J. ; Lee, J. G. ; Lee, C. Y. ; Hong, M. H. ; Kim, S. M. ; Kim, H. ; Pyo, K. H. ; Yun, M. R. ; Park, H. J. ; Han, J. Y. ; Youn, H. A. ; Ahn, M. J. ; Paik, S. ; Kim, T. M. ; Cho, B. C. / Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma. In: Annals of Oncology. 2017 ; Vol. 28, No. 6. pp. 1250-1259.
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title = "Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma",
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 to in 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 of FGFR1-3 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 SHCmediated 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.",
author = "Kim, {H. R.} and Kang, {H. N.} and Shim, {H. S.} and Kim, {E. Y.} and J. Kim and Kim, {D. J.} and Lee, {J. G.} and Lee, {C. Y.} and Hong, {M. H.} and Kim, {S. M.} and H. Kim and Pyo, {K. H.} and Yun, {M. R.} and Park, {H. J.} and Han, {J. Y.} and Youn, {H. A.} and Ahn, {M. J.} and S. Paik and Kim, {T. M.} and Cho, {B. C.}",
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Kim, HR, Kang, HN, Shim, HS, Kim, EY, Kim, J, Kim, DJ, Lee, JG, Lee, CY, Hong, MH, Kim, SM, Kim, H, Pyo, KH, Yun, MR, Park, HJ, Han, JY, Youn, HA, Ahn, MJ, Paik, S, Kim, TM & Cho, BC 2017, 'Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma', Annals of Oncology, vol. 28, no. 6, mdx098, pp. 1250-1259. https://doi.org/10.1093/annonc/mdx098

Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma. / Kim, H. R.; Kang, H. N.; Shim, H. S.; Kim, E. Y.; Kim, J.; Kim, D. J.; Lee, J. G.; Lee, C. Y.; Hong, M. H.; Kim, S. M.; Kim, H.; Pyo, K. H.; Yun, M. R.; Park, H. J.; Han, J. Y.; Youn, H. A.; Ahn, M. J.; Paik, S.; Kim, T. M.; Cho, B. C.

In: Annals of Oncology, Vol. 28, No. 6, mdx098, 01.06.2017, p. 1250-1259.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma

AU - Kim, H. R.

AU - Kang, H. N.

AU - Shim, H. S.

AU - Kim, E. Y.

AU - Kim, J.

AU - Kim, D. J.

AU - Lee, J. G.

AU - Lee, C. Y.

AU - Hong, M. H.

AU - Kim, S. M.

AU - Kim, H.

AU - Pyo, K. H.

AU - Yun, M. R.

AU - Park, H. J.

AU - Han, J. Y.

AU - Youn, H. A.

AU - Ahn, M. J.

AU - Paik, S.

AU - Kim, T. M.

AU - Cho, B. C.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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 to in 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 of FGFR1-3 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 SHCmediated 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.

AB - 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 to in 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 of FGFR1-3 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 SHCmediated 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.

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U2 - 10.1093/annonc/mdx098

DO - 10.1093/annonc/mdx098

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JO - Annals of Oncology

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