Supplementary Table S1-S2 and Figure S1-S2 from Oncogenic Characterization and Pharmacologic Sensitivity of Activating Fibroblast Growth Factor Receptor (FGFR) Genetic Alterations to the Selective FGFR Inhibitor Erdafitinib

Karkera, Jayaprakash D.; Cardona, Gabriela Martinez; Bell, Katherine; Gaffney, Dana; Portale, Joseph C.; Santiago-Walker, Ademi; Moy, Christopher H.; King, Peter; Sharp, Michael; Bahleda, Rastislav; Luo, Feng R.; Alvarez, John D.; Lorenzi, Matthew V.; Platero, Suso J.

doi:10.1158/1535-7163.22509070.v1

15357163mct160518-sup-168212_3_unknown_upload_3954332_fnfxwx.doc (160.5 kB)

Supplementary Table S1-S2 and Figure S1-S2 from Oncogenic Characterization and Pharmacologic Sensitivity of Activating Fibroblast Growth Factor Receptor (FGFR) Genetic Alterations to the Selective FGFR Inhibitor Erdafitinib

journal contribution

posted on 2023-04-03, 15:52 authored by Jayaprakash D. Karkera, Gabriela Martinez Cardona, Katherine Bell, Dana Gaffney, Joseph C. Portale, Ademi Santiago-Walker, Christopher H. Moy, Peter King, Michael Sharp, Rastislav Bahleda, Feng R. Luo, John D. Alvarez, Matthew V. Lorenzi, Suso J. Platero

Table S1. Frequencies of gene locus amplifications across tumor types; Table S2. Effect of FGFR inhibitors on growth of RK3E expressing FGFR2 and FGFR3 fusion constructs and RT-4 bladder cancer cell line; Figure S1. Chemical structure of JNJ-42756493; Figure S2. Western Blot confirming the overexpression of HA-tagged FGFR2 fusion genes

Funding

Janssen Research and Development, LLC

History

ARTICLE ABSTRACT

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.