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

Deukchae Na, Jeesoo Chae, Sung-Yup Cho, Wonyoung Kang, Ahra Lee, Seoyeon Min, Jinjoo Kang, Min Jung Kim, Jaeyong Choi, Woochan Lee, Dongjin Shin, Ahrum Min, Yu-Jin Kim, Kyung-Hun Lee, Tae-Yong Kim, Yun-Suhk Suh, Seong-Ho Kong, Hyuk-Joon Lee, Woo-Ho Kim, Hansoo Park, Seock-Ah Im (), Han-Kwang Yang (), Charles Lee () and Jong-Il Kim ()
Additional contact information
Deukchae Na: Ewha Womans University Mokdong Hospital
Jeesoo Chae: Seoul National University College of Medicine
Sung-Yup Cho: Seoul National University College of Medicine
Wonyoung Kang: The Jackson Laboratory for Genomic Medicine
Ahra Lee: Ewha Womans University
Seoyeon Min: Ewha Womans University
Jinjoo Kang: Ewha Womans University
Min Jung Kim: Seoul National University
Jaeyong Choi: Seoul National University College of Medicine
Woochan Lee: Seoul National University College of Medicine
Dongjin Shin: Seoul National University College of Medicine
Ahrum Min: Seoul National University
Yu-Jin Kim: Seoul National University
Kyung-Hun Lee: Seoul National University
Tae-Yong Kim: Seoul National University
Yun-Suhk Suh: Seoul National University College of Medicine
Seong-Ho Kong: Seoul National University College of Medicine
Hyuk-Joon Lee: Seoul National University
Woo-Ho Kim: Seoul National University
Hansoo Park: Gwangju Institute of Science and Technology (GIST)
Seock-Ah Im: Seoul National University
Han-Kwang Yang: Seoul National University
Charles Lee: The Jackson Laboratory for Genomic Medicine
Jong-Il Kim: Seoul National University College of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25122-4

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