PMID- 28460066 OWN - NLM STAT- MEDLINE DCOM- 20180129 LR - 20221207 IS - 1569-8041 (Electronic) IS - 0923-7534 (Linking) VI - 28 IP - 6 DP - 2017 Jun 1 TI - Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma. PG - 1250-1259 LID - 10.1093/annonc/mdx098 [doi] 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 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. CI - (c) The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. FAU - Kim, H R AU - Kim HR AD - Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul. FAU - Kang, H N AU - Kang HN AD - JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk. FAU - Shim, H S AU - Shim HS AD - Departments of Pathology. FAU - Kim, E Y AU - Kim EY AD - Pulmonology, Yonsei University College of Medicine, Seoul. FAU - Kim, J AU - Kim J AD - Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul. FAU - Kim, D J AU - Kim DJ AD - Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul. FAU - Lee, J G AU - Lee JG AD - Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul. FAU - Lee, C Y AU - Lee CY AD - Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul. FAU - Hong, M H AU - Hong MH AD - Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul. FAU - Kim, S-M AU - Kim SM AD - JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk. FAU - Kim, H AU - Kim H AD - JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk. FAU - Pyo, K-H AU - Pyo KH AD - JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk. FAU - Yun, M R AU - Yun MR AD - JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk. FAU - Park, H J AU - Park HJ AD - JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk. FAU - Han, J Y AU - Han JY AD - JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk. FAU - Youn, H A AU - Youn HA AD - JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk. FAU - Ahn, M-J AU - Ahn MJ AD - Division of Hematology & Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. FAU - Paik, S AU - Paik S AD - Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul. FAU - Kim, T-M AU - Kim TM AD - Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea. FAU - Cho, B C AU - Cho BC AD - Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul. AD - JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk. LA - eng PT - Journal Article PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - 0 (4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one) RN - 0 (Benzimidazoles) RN - 0 (Biomarkers) RN - 0 (Quinolones) RN - 0 (Receptors, Fibroblast Growth Factor) SB - IM MH - Benzimidazoles/*therapeutic use MH - Biomarkers/*blood MH - Carcinoma, Squamous Cell/*drug therapy/genetics MH - *Clinical Trials as Topic MH - Humans MH - Lung Neoplasms/*drug therapy/genetics MH - Mutation MH - Quinolones/*therapeutic use MH - Receptors, Fibroblast Growth Factor/*antagonists & inhibitors/metabolism MH - Signal Transduction MH - Exome Sequencing OTO - NOTNLM OT - *biomarker OT - *dovitinib OT - *fibroblast growth factor receptor OT - *patient-derived xenograft OT - *squamous cell lung cancer EDAT- 2017/05/02 06:00 MHDA- 2018/01/30 06:00 CRDT- 2017/05/02 06:00 PHST- 2017/05/02 06:00 [pubmed] PHST- 2018/01/30 06:00 [medline] PHST- 2017/05/02 06:00 [entrez] AID - S0923-7534(19)32427-5 [pii] AID - 10.1093/annonc/mdx098 [doi] PST - ppublish SO - Ann Oncol. 2017 Jun 1;28(6):1250-1259. doi: 10.1093/annonc/mdx098.