Evaluation of treatment with Nintedanib in patients with idiopathic pulmonary fibrosis: a proteomical approach

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal progressive disease with a median survival of 2-5 years. Nintedanib is a small tyrosine kinase inhibitor that reduces IPF progression, slowing the annual decline in Forced Vital Capacity. Very little data is available on the molecular mechanisms of this treatment in IPF, despite a growing interest in the definition of IPF pathogenesis and target therapy. Objective: A functional proteomic approach was applied to the analysis of serum samples from IPF patients to highlight biomarkers indicative of drug-induced molecular pathway modifications and response to therapy. Methods: 12 serum samples were collected from 6 IPF patients in care at Siena Regional Referral Center for Interstitial Lung Diseases and treated with Nintedanib for one year. Serum samples were analyzed at baseline (T0 before starting therapy) and after one year of treatment (T1) and underwent differential proteomic and bioinformatic analysis. Results: Proteomic analysis revealed 13 protein species that were significantly increased at T1. When the targets of Nintedanib (VEGFR, FGFR and PDGFR) were added, enrichment analysis extracted molecular pathways and process networks involved in cell differentiation (haptoglobin and albumin), coagulation (antithrombin III), epithelial mesenchymal transition, cell proliferation and transmigration. PI3K and MAPK induced up-regulation of apolipoprotein C3. Conclusions: Proteomic study found 13 protein species up-regulated in IPF patients after one year of Nintedanib treatment. These theranostic markers will be validated quantitatively in a more numerous population of patients by easy to perform, widely available methods.