XBP1 promoter polymorphism modulates platinum-based chemotherapy gastrointestinal toxicity for advanced non-small cell lung cancer patients

BackgroundThe X-box binding protein 1 (XBP1) is a critical transcription factor in the endoplasmic reticulum stress response, which is essential for the maintenance of cellular homeostasis. Here, we investigated whether the regulatory variant rs2269577 of the XBP1 gene influences clinical outcome in advanced non-small cell lung cancer (NSCLC) patients undergoing platinum-based chemotherapy.Patients and methodsWe recruited 663 Chinese patients with advanced NSCLC treated with platinum-based regimens and assessed the association between rs2269577 and clinical outcome. Subsequent functional analyses, including real-time quantitative PCR and dual-luciferase assays, were performed to explore possible molecular mechanisms.ResultsThe G/G genotype of rs2269577 was significantly associated with severe gastrointestinal toxicity compared with the homozygous C/C genotype (P = 0.012, odds ratio = 2.755), particularly in the female, performance status 0–1, and adenocarcinoma subgroups. No significant relevance was found between rs2269577 and treatment efficacy. In gastric epithelial cells, in vitro molecular analyses demonstrated that XBP1 mRNA expression levels decreased after treatment with cisplatin and the G allele of rs2269577 weakened the transcriptional activity of the XBP1 promoter.ConclusionThis is the first study to evaluate the effect of XBP1 polymorphism on severe chemotherapy-related adverse outcomes in platinum-treated advanced NSCLC patients using both pharmacogenomics and functional molecular analyses.