PI3/Elafin expression predicts recurrence after chemotherapy with DNA-damaging drugs in gastric cancer

ABSTRACT: Despite recent advances in gastric cancer therapy, chemotherapy resistance and lack of methods for selecting combination regimens remain major problems. Organoids, which recapitulate the in vivo micro-environment, can be established from surgical specimens with a high success rate, and are widely used for drug sensitivity assays. In this study, we aimed to discover a novel biomarker for predicting multidrug resistance using gastric cancer organoids (GCOs), which provide in vivo-like culture system that more closely resembles tumor cell organization than traditional cell lines. We evaluated 5-fluorouracil or oxaliplatin-resistant GCOs to find novel biomarkers that reflect multidrug resistance in gastric cancer. To examine the resistance mechanisms, RNA-seq analysis and ex vivo drug sensitivity testing were performed. The association of biomarkers with patient prognosis and chemotherapy efficacy was evaluated using three original cohorts with a total of 230 cases. The results were also validated with two independent public cohorts and a single-cell RNA sequence data. Increased expression of PI3/Elafin was detected in all 5-fluorouracil or oxaliplatin-resistant GCOs. Our findings suggest a potential association of PI3/Elafin expression with ribosome biosynthesis and RNA metabolism under organoid conditions. We also found that PI3/Elafin overexpression promotes 5-fluorouracil/oxaliplatin/cisplatin resistance but not paclitaxel resistance. Immunohistochemical evaluation of Elafin expression revealed that the Elafin-positive gastric cancer group had a poorer outcome, especially in terms of time-to-recurrence. Elafin positivity was also an independent predictor of relapse after chemotherapy with DNA-damaging agents. PI3/Elafin promotes DNA-damaging drug resistance through multiple downstream regulations related to RNA and ribosomal metabolism. PI3/Elafin may be useful as a biomarker for therapeutic selection of non-DNA-damaging agents.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280755 | GEO | 2024/12/25

REPOSITORIES: GEO