Predictive biomarkers for 5-fluorouracil and oxaliplatin-based chemotherapy in gastric cancers via profiling of patient-derived xenografts

• Published in: Nature communications Vol. 12; no. 1; pp. 4840 - 14
• Main Authors: Na, Deukchae, Chae, Jeesoo, Cho, Sung-Yup, Kang, Wonyoung, Lee, Ahra, Min, Seoyeon, Kang, Jinjoo, Kim, Min Jung, Choi, Jaeyong, Lee, Woochan, Shin, Dongjin, Min, Ahrum, Kim, Yu-Jin, Lee, Kyung-Hun, Kim, Tae-Yong, Suh, Yun-Suhk, Kong, Seong-Ho, Lee, Hyuk-Joon, Kim, Woo-Ho, Park, Hansoo, Im, Seock-Ah, Yang, Han-Kwang, Lee, Charles, Kim, Jong-Il
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 10.08.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: 5-Fluorouracil; Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers; Biomarkers, Tumor - genetics; Cancer; Chemotherapy; Decision making; Extracellular matrix; Female; Fluorouracil - administration & dosage; Gastric cancer; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic - drug effects; Humans; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Oxaliplatin; Oxaliplatin - administration & dosage; Patients; Platinum; Prediction models; Predictions; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Survival Analysis; Tumor Burden - drug effects; Tumor Burden - genetics; Tumor microenvironment; Tumors; Xenograft Model Antitumor Assays - methods; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25122-4

Gastric cancer (GC) is commonly treated by chemotherapy using 5-fluorouracil (5-FU) derivatives and platinum combination, but predictive biomarker remains lacking. We develop patient-derived xenografts (PDXs) from 31 GC patients and treat with a combination of 5-FU and oxaliplatin, to determine biomarkers associated with responsiveness. When the PDXs are defined as either responders or non-responders according to tumor volume change after treatment, the responsiveness of PDXs is significantly consistent with the respective clinical outcomes of the patients. An integrative genomic and transcriptomic analysis of PDXs reveals that pathways associated with cell-to-cell and cell-to-extracellular matrix interactions enriched among the non-responders in both cancer cells and the tumor microenvironment (TME). We develop a 30-gene prediction model to determine the responsiveness to 5-FU and oxaliplatin-based chemotherapy and confirm the significant poor survival outcomes among cases classified as non-responder-like in three independent GC cohorts. Our study may inform clinical decision-making when designing treatment strategies.