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.
Highlights
The successful development of new oncology therapies most unequivocally requires identifying the patients most likely to respond to a particular targeted intervention
Cell lines harboring fibroblast growth factor receptor (FGFR) alterations were dependent on the active pathway for survival and sensitive to treatment with erdafitinib. We extended this characterization to FGFR2 and FGFR3 chromosomal rearrangements recently identified in human tumors [26], highlighting the oncogenic potency of these fusions and their sensitivity to FGFR inhibition
Predictive and pharmacodynamic biomarkers SNU-16 cells, which carry a high-level FGFR2 amplification, were sensitive to the FGFR inhibitor JNJ-42883919, and FGFR phosphoprotein levels decreased upon treatment with the study drug, as measured by immunohistochemical staining of formalin-fixed paraffin-embedded (FFPE) tumor cells (Fig. 1A and B)
Summary
The successful development of new oncology therapies most unequivocally requires identifying the patients most likely to respond to a particular targeted intervention. The discovery and characterization of biomarkers that accurately distinguish those more likely to respond patients from a broader population is critical for successful clinical development. Examples of such biomarkers that have already been identified and approved as predictors of response to therapy include human epidermal. Fibroblast growth factor receptor (FGFR)-mediated signaling has been shown to play a role in tumor progression, and recent evidence suggests that FGFRs are oncogenic drivers in various types of cancer [6], highlighting the need to find predictive biomarkers of FGFR to support clinical development
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