(208) Pharmacovigilance Analysis of Immune-Related Adverse Effects to Uncover Repurposable Drugs for Hepatocellular Carcinoma

Background: This study is grounded in the concept that drugs sharing common side effects may possess similar mechanisms in addressing specific diseases. Immune-related Adverse Effects (irAEs) encompass a unique spectrum of negative outcomes stemming from the overstimulation of the immune system, a prominent side effect of immune checkpoint inhibitors.

Objectives: Our study aims to investigate repurposable drugs for HepatoCellular Carcinoma (HCC) by identifying those exhibiting side effect profiles analogous to immune checkpoint inhibitors.

Methods: We conducted a case/non-case retrospective disproportionality analysis using the publicly available FAERS database, employing OpenVigil 2.1 (2004Q1-2022Q4). Reporting odds ratio (ROR) and Proportional reporting ratio (PRR) served as the measure of disproportionality. A signal threshold set at ROR-1.96SE > 1, beyond which was considered as a positive signal. To validate our hypothesis, we employed the MTT assay to assess the cytotoxicity of the identified drug. Flow cytometry analysis was utilized to ascertain the proportion of cells arrested in distinct cell cycle phases.

Results: We identified Etravirine with 20 irAEs, encompassing 170 reports, with peripheral neuropathy (n=24) being the most frequently reported irAE. Ten irAEs (stevens-Johnson syndrome, thrombocytopenia, hepatitis, pancreatitis, tubulointerstitial nephritis, myositis, uveitis, neuropathy peripheral, adrenal suppression, nephropathy) met the criteria for positive signals, with the highest signal strength observed for adrenal suppression (ROR (95% CI) = 118.029 (66.407-209.779)). In this study, we hypothesize that the anticancer potential of etravirine might resemble that of immune checkpoint inhibitors, as indicated by these signals. Moreover, Etravirine exhibited cytotoxicity against the Huh7 cell line at a dose of 60.37 µM/mL. At the respective IC50 concentration, the etravirine-treated cell lines showed an arrest of 13.04% of cells in the Sub G0/G1 phase. In the S phase, 7.17% of cells, and in the G2/M phase 41.73% of cells were arrested associated with apoptosis.

Conclusions: Etravirine exhibited a similar spectrum of AEs as that of immune checkpoint inhibitors, which gave us a hypothesis of the anticancer potential of Etravirine. The cytotoxicity and cell cycle analysis of Etravirine enforces this hypothesis. However, further research is required to confirm the same.