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|Ref Type||Journal Article|
|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|
|Date||2013 Jul 01|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Dovitinib||TKI258|CHIR-258||CSF1R Inhibitor 28 FGFR Inhibitor (Pan) 25 FLT3 Inhibitor 62 KIT Inhibitor 56 PDGFR Inhibitor (Pan) 28 VEGFR Inhibitor (Pan) 35||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 II||Actionable||In a Phase II trial, Dovitinib (TKI258) promoted 6-month stable disease in Erbb2 (Her2)-positive breast cancer patients with FGFR1 amplification (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|
|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|