The correlation of two SNPs in the DRACHmotif with gefitinib-induced hepatotoxicity in patients with non-small cell lung cancer.

e20644 Background: Drug-induced liver injury (DILI) represents a significant safety concern in drug development and clinical therapy. Severe hepatotoxicity of gefitinib often leads to acute/chronic liver injury, which can result in drug discontinuation and subsequent treatment failure. However, the underlying mechanisms of gefitinib-induced hepatotoxicity remain poorly understood. N6-Methyladenosine (m6A) modification plays a crucial role in maintaining normal hepatic function and single nucleotide polymorphisms (SNPs) in the conserved DRACH motif may influence m6A expression levels and gene regulation, potentially affecting drug response. This study aimed to explore the correlation between SNPs in the DRACH motif and gefitinib-induced hepatotoxicity in patients with advanced non-small cell lung cancer (NSCLC). Methods: A total of 41 candidate SNPS were selected through screening of the RMVar database and their association with gefitinib-induced hepatotoxicity was analyzed using Chi-square test and Fisher's exact test in 174 advanced NSCLC patients, 86 of whom suffered from hepatotoxicity. Furthermore, the functions of the relative SNPs were identified by RNAfold. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: The association of two SNPs, PPARGC1A rs2970847 and MCUB rs3733611, in the DRACH motif and gefitinib-induced hepatotoxicity were identified. TT carriers of PPARGC1A rs2970847 had an increased risk of developing gefitinib - induced hepatotoxicity compared to CC/CT carriers ( P = 0.044, OR = 2.177, 95%CI (1.022-4.639)).And it is worth noting that all TT-type patients (n = 7) in the cohort developed hepatotoxicity. Using RNAfold for RNA secondary structure prediction, the results indicate that the RNA stability of the PPARGC1A rs2970847 TT genotype is relatively low, which may lead to reduced gene expression and is associated with the high incidence of hepatotoxicity in patients with this genotype. Meanwhile, patients with MCUB rs3733611 CT had higher risk of hepatotoxicity ( P = 0.041, OR= 2.517, CI%(1.038-6.100)). Conclusions: PPARGC1A rs2970847 and MCUB rs3733611 serve as potential predictive biomarkers for gefitinib-induced hepatotoxicity in NSCLC patients. Further investigations into the mechanisms underlying the association between 2 SNPs in the DRACH motif and gefitinib-induced hepatotoxicity are warranted. Clinical trial information: NCT01994057 .