Interactions of Kidney Function Related Genes and Proteins with Anticancer Drugs and Strategies to Mitigate their Adverse Effects

Overview

Sorafenib, an antiangiogenic multikinase inhibitor (MKI) used in the treatment of renal carcinoma has been linked to the development of focal segmental glomerulosclerosis (FSGS) due to inhibition of proliferation related signaling via the vascular endothel ial growth factor receptors (VEGFRs) (Wen et al., 2018). Sorafenib’s nephrotoxic properties also lead to dysregulation of differential gene expressions leading to the upregulation or inhibition of vital kidney survival related pathways. Epoxyeicosatrienoic acids (EETs), are a group of endogenous fatty acids that have protective properties including pro -angiogenesis, counteracting sorafenib -induced renal dysfunction (Imig, 2015). This study aims to study pathways responsible for sorafenib -induced FSGS progression and seeks to explore preventative strategies using the protective drug 8, 9 EET analog. It was hypothesized that vital kidney function related genes are responsible for the development of FSGS, and 8, 9 EET analog has protective properties that can counteract damaging pathways. Using the Nephroseq database, significantly dysregulated genes were obtained and screened via hierarchal clustering. Data was then uploaded to the QIAGEN IPA application, in which an ingenuity pathway analysis was conducted re vealing key pathways responsible for FSGS development. These findings were further validated through in vitro experiments and genomic studies. This research revealed that sorafenib-induced FSGS is driven by an increase in inflammatory and oxidative stress pathways, resulting in further progression of fibrosis in the glomerulus. Genomic studies supported 8, 9 EET analog’s protective properties, and its ability to regulate differential gene expressions, allowing it to counteract effects of sorafenib on oxidative stress and inflammation related pathways.