FOXO3 polymorphisms were correlated with gefitinib-induced hepatotoxicity in patients with non-small cell lung cancer.

Abstract

9578 Background: Drug-induced liver injury (DILI) is one of the most safety concern in drug development and clinical therapy. Severe hepatotoxicity of gefitinib often leads to acute/chronic liver injury, drug discontinuation and further treatment failure, however, the mechanism of gefitinib-induced hepatotoxicity remains unclear. AKT1/FOXO3 regulates expression of genes involved in multiple biological/pathological processes in liver cells, including apoptosis, oxidative stress, and cell-cycle transition, as well as expression of autophagy-related (Atg) genes. Therefore, we investigated the correlation between single nucleotide polymorphisms (SNP) in AKT1/ FOXO3 and gefitinib-induced hepatotoxicity in patients with advanced non-small cell lung cancer (NSCLC). Methods: A total of 172 advanced NSCLC patients with activating EGFR mutations were enrolled and administered with gefitinib 250mg daily. 22 tag SNPs in AKT1/FOXO3 were selected by Heploview 4.2 and sequenced by Agena MassARRAY System. The associations between polymorphisms of AKT1/FOXO3 and gefitinib-induced hepatotoxicity were analyzed by Chi square test. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: FOXO3 rs4946935 and FOXO3 rs75544369 were found to be associated with gefitinib-induced hepatotoxicity in NSCLC patients. FOXO3 rs4946935 AA carriers have higher risk of developing gefitinib-induced hepatotoxicity than those with FOXO3 rs4946935 AG/GG. ( P = 0.018, OR = 12.414, 95%CI (1.53-100.711)). Patients with FOXO3 rs75544369 GA have higher risk of developing hepatotoxicity with P of 0.0002 (OR = 5.241, CI%(1.85-14.851)), or developing severe hepatotoxicity with P of 0.033 (OR = 2.963, 95%CI (1.090-8.059)), than those with FOXO3 rs75544369 GG. Conclusions: FOXO3 rs4946935 and FOXO3 rs75544369 are predictive biomarkers for gefitinib-induced hepatotoxicity in NSCLC patients. The mechanism underlying the association between FOXO3 polymorphisms and gefitinib-induced hepatotoxicity are worth investigating in further studies. Clinical trial information: NCT01994057 .