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Ref Type Journal Article
PMID (28416604)
Authors Karkera JD, Cardona GM, Bell K, Gaffney D, Portale JC, Santiago-Walker A, Moy CH, King P, Sharp M, Bahleda R, Luo FR, Alvarez JD, Lorenzi MV, Platero SJ
Title Oncogenic Characterization and Pharmacologic Sensitivity of Activating Fibroblast Growth Factor Receptor (FGFR) Genetic Alterations to the Selective FGFR Inhibitor Erdafitinib.
Journal Molecular cancer therapeutics
Vol 16
Issue 8
Date 2017 08
URL
Abstract Text Fibroblast growth factor receptor (FGFR) genetic alterations are frequently observed in cancer, suggesting that FGFR inhibition may be a promising therapy in patients harboring these lesions. Identification of predictive and pharmacodynamic biomarkers to select and monitor patients most likely to respond to FGFR inhibition will be the key to clinical development of this class of agents. Sensitivity to FGFR inhibition and correlation with FGFR pathway activation status were determined in molecularly annotated panels of cancer cell lines and xenograft models. Pathway inhibition in response to FGFR inhibitor treatment was assessed in cell lines (both in vitro and in vivo) and in samples from patients treated with the FGFR inhibitor JNJ-42756493 (erdafitinib). Frequency of FGFR aberrations was assessed in a panel of NSCLC, breast, prostate, ovarian, colorectal, and melanoma human tumor tissue samples. FGFR translocations and gene amplifications present in clinical specimens were shown to display potent transforming activity associated with constitutive pathway activation. Tumor cells expressing these FGFR activating mutants displayed sensitivity to the selective FGFR inhibitor erdafitinib and resulted in suppression of FGFR phosphorylation and downstream signal transduction. Clinically, patients receiving erdafitinib showed decreased Erk phosphorylation in tumor biopsies and elevation of serum phosphate. In a phase I study, a heavily pretreated bladder cancer patient with an FGFR3-TACC3 translocation experienced a partial response when treated with erdafitinib. This preclinical study confirmed pharmacodynamics and identified new predictive biomarkers to FGFR inhibition with erdafitinib and supports further clinical evaluation of this compound in patients with FGFR genetic alterations. Mol Cancer Ther; 16(8); 1717-26. ©2017 AACR.

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 AFF3 FGFR2 - AFF3 fusion gain of function FGFR2-AFF3 results from the fusion of FGFR2 and AFF3 (PMID: 23558953), leading to activation of Fgfr downstream signaling and transformation in culture (PMID: 28416604). FGFR2-AFF3 has been identified in breast cancer (PMID: 23558953).
FGFR2 BICC1 FGFR2 - BICC1 fusion gain of function FGFR2-BICC1 results from the fusion of FGFR2 and BICC1, resulting in the ability to induce oligomerization, Fgfr kinase activity, Mapk signaling and transformation of cells in culture and in animal models (PMID: 23558953, PMID: 24122810, PMID: 28416604). FGFR2-BICC1 has been identified in intrahepatic cholangiocarcinoma (PMID: 25608663, PMID: 31899106).
FGFR2 CASP7 FGFR2 - CASP7 fusion gain of function FGFR2-CASP7 results from the fusion of FGFR2 and CASP7 (PMID: 23558953), leading to activation of Fgfr downstream signaling and transformation in culture (PMID: 28416604). FGFR2-CASP7 has been identified in breast cancer (PMID: 23558953).
FGFR2 CCDC6 FGFR2 - CCDC6 fusion gain of function FGFR2-CCDC6 results from the fusion of FGFR2 and CCDC6, resulting in the ability to induce oligomerization, activate Fgfr kinase activity, and induce cell proliferation (PMID: 23558953), and is transforming in culture (PMID: 28416604). FGFR2-CCDC6 has been identified in cholangiocarcinoma (PMID: 27216979).
FGFR2 OFD1 FGFR2 - OFD1 fusion gain of function FGFR2-OFD1 results from the fusion of FGFR2 and OFD1 (PMID: 23558953), leading to activation of Fgfr downstream signaling and transformation in culture (PMID: 28416604). FGFR2-OFD1 has been identified in thyroid carcinoma (PMID: 23558953).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 - CCDC6 Advanced Solid Tumor sensitive Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, Balversa (erdafitinib) inhibited Fgfr phosphorylation and downstream signaling, resulted in growth inhibition of transformed cells expressing FGFR2-CCDC6 in culture (PMID: 28416604). 28416604
FGFR2 - AFF3 Advanced Solid Tumor sensitive Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, Balversa (erdafitinib) inhibited Fgfr phosphorylation and downstream signaling, resulted in growth inhibition of transformed cells expressing FGFR2-AFF3 in culture (PMID: 28416604). 28416604
FGFR2 - BICC1 Advanced Solid Tumor sensitive Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, Balversa (erdafitinib) inhibited Fgfr phosphorylation and downstream signaling, resulted in growth inhibition of transformed cells expressing FGFR2-BICC1 in culture (PMID: 28416604). 28416604
FGFR3 - BAIAP2L1 Advanced Solid Tumor sensitive Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, Balversa (erdafitinib) inhibited Fgfr phosphorylation and downstream signaling, resulted in growth inhibition of transformed cells expressing FGFR3-BAIA2PL1 in culture (PMID: 28416604). 28416604
FGFR2 - CASP7 Advanced Solid Tumor sensitive Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, Balversa (erdafitinib) inhibited Fgfr phosphorylation and downstream signaling, resulted in growth inhibition of transformed cells expressing FGFR2-CASP7 in culture (PMID: 28416604). 28416604
FGFR2 - OFD1 Advanced Solid Tumor sensitive Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, Balversa (erdafitinib) inhibited Fgfr phosphorylation and downstream signaling, resulted in growth inhibition of transformed cells expressing FGFR2-OFD1 in culture (PMID: 28416604). 28416604
FGFR3 - TACC3 urinary bladder cancer predicted - sensitive Erdafitinib Case Reports/Case Series Actionable In a Phase I trial, Balversa (erdafitinib) treatment resulted in a partial response with 38% shrinkage of tumor in a patient with metastatic bladder cancer harboring FGFR3-TACC3, who stayed on treatment for 10 months (PMID: 28416604; NCT01703481). 28416604