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

IF 5.6 2区医学 Q1 ONCOLOGY The Journal of Pathology Pub Date : 2025-02-20 DOI:10.1002/path.6400

Kenji Harada, Naoya Sakamoto, Takumi Kitaoka, Yuka Nakamura, Ryotaro Kondo, Ryo Morisue, Hiroko Hashimoto, Yusuke Yamamoto, Shoichi Ukai, Ryota Maruyama, Shingo Sakashita, Motohiro Kojima, Kazuaki Tanabe, Hideki Ohdan, Kohei Shitara, Takahiro Kinoshita, Genichiro Ishii, Wataru Yasui, Atsushi Ochiai, Shumpei Ishikawa

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引用次数: 0

Abstract

Despite recent advances in gastric cancer therapy, chemotherapy resistance and lack of methods for selecting combination regimens remain major problems. Organoids, which provide a culture system that more closely resembles tumor cell organization than traditional cell lines, 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 identify a novel biomarker for predicting multidrug resistance using gastric cancer organoids (GCOs). 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-sequencing 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 single-cell RNA sequence data. Increased expression of peptidase inhibitor 3 (PI3) was detected in all 5-fluorouracil or oxaliplatin-resistant GCOs. Our findings suggest a potential association of PI3 expression with ribosome biosynthesis and RNA metabolism under organoid conditions. We also found that PI3 overexpression promoted 5-fluorouracil/oxaliplatin/cisplatin resistance but not paclitaxel resistance. Immunohistochemical evaluation of PI3 expression revealed that the PI3-positive gastric cancer group had a poorer outcome, especially in terms of time to recurrence. PI3 positivity was also an independent predictor of relapse after chemotherapy with DNA-damaging agents. PI3 promotes DNA-damaging drug resistance through multiple downstream regulations related to RNA and ribosomal metabolism. PI3 may be useful as a biomarker for the therapeutic selection of non-DNA-damaging agents. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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来源期刊

The Journal of Pathology 医学-病理学

CiteScore

14.10

自引率

1.40%

发文量

144

审稿时长

3-8 weeks

期刊介绍： The Journal of Pathology aims to serve as a translational bridge between basic biomedical science and clinical medicine with particular emphasis on, but not restricted to, tissue based studies. The main interests of the Journal lie in publishing studies that further our understanding the pathophysiological and pathogenetic mechanisms of human disease. The Journal of Pathology welcomes investigative studies on human tissues, in vitro and in vivo experimental studies, and investigations based on animal models with a clear relevance to human disease, including transgenic systems. As well as original research papers, the Journal seeks to provide rapid publication in a variety of other formats, including editorials, review articles, commentaries and perspectives and other features, both contributed and solicited.