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Ref Type Journal Article
PMID (23658459)
Authors André F, Bachelot T, Campone M, Dalenc F, Perez-Garcia JM, Hurvitz SA, Turner N, Rugo H, Smith JW, Deudon S, Shi M, Zhang Y, Kay A, Porta DG, Yovine A, Baselga J
Title Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 19
Issue 13
Date 2013 Jul 01
URL
Abstract Text Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers.Preclinical activity of dovitinib was evaluated in both breast cancer cell lines and an FGFR1-amplified xenograft model (HBCx2). Dovitinib was then evaluated in a phase II trial that included 4 groups of patients with human EGF receptor 2-negative metastatic breast cancer on the basis of FGFR1 amplification and hormone receptor (HR) status. FGFR1 amplification was assessed by silver in situ hybridization. Preplanned retrospective analyses assessed predictive value of FGFR1, FGFR2, and FGF3 amplifications by quantitative PCR (qPCR).Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2-amplified, but not FGFR-normal, breast cancer cell lines. Dovitinib also inhibits tumor growth in FGFR1-amplified breast cancer xenografts. Eighty-one patients were enrolled in the trial. Unconfirmed response or stable disease for more than 6 months was observed in 5 (25%) and 1 (3%) patient(s) with FGFR1-amplified/HR-positive and FGFR1-nonamplified/HR-positive breast cancer. When qPCR-identified amplifications in FGFR1, FGFR2, or FGF3 were grouped to define an FGF pathway-amplified breast cancer in HR-positive patients, the mean reduction in target lesions was 21.1% compared with a 12.0% increase in patients who did not present with FGF pathway-amplified breast cancer.Dovitinib showed antitumor activity in FGFR-amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Dovitinib Dovitinib 55 16
Drug Name Trade Name Synonyms Drug Classes Drug Description
Dovitinib TKI258|CHIR-258 CSF1R Inhibitor 24 FGFR Inhibitor (Pan) 18 FLT3 Inhibitor 55 KIT Inhibitor 51 PDGFR Inhibitor (Pan) 27 VEGFR Inhibitor (Pan) 32 Dovitinib (TKI258) targets multiple receptor tyrosine kinases including Flt3, c-Kit, CSF1R, FGFR 1-4, VEGFR 1-3, and PDGFR alpha and beta, potentially resulting in decreased tumor growth (PMID: 15598814, PMID: 25219510, PMID: 23658459, PMID: 16033847).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 amp Her2-receptor positive breast cancer sensitive Dovitinib Phase I Actionable In a Phase I trial, Dovitinib (TKI258) promoted 6-month stable disease in Erbb2 (Her2)-positive breast cancer patients with FGFR1 amplification (PMID: 23658459). 23658459
FGFR2 amp Her2-receptor positive breast cancer sensitive Dovitinib Phase I Actionable In a Phase I trial, Dovitinib (TKI258) displayed safety and preliminary efficacy resulting in tumor regression of 28.2% and 18.5% in two patients with FGFR2 amplified Erbb2 (Her2)-receptor positive breast cancer (PMID: 23658459). 23658459
FGFR2 amp breast cancer sensitive Dovitinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Dovitinib (TKI258) inhibited cell growth of an FGFR2 amplified breast cancer cell line in culture and prevented tumor growth and induced tumor regression in FGFR2 amplified breast cancer patient derived xenograft (PDX) models (PMID: 23658459). 23658459