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Cited by 135Gastric Cancer Management and OutcomesColorectal Cancer Treatments and StudiesBreast Cancer Treatment Studies

A Gene Expression Signature of Acquired Chemoresistance to Cisplatin and Fluorouracil Combination Chemotherapy in Gastric Cancer Patients

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Kim, Hark Kyun, Choi, Il Ju, Kim, Chan Gyoo, Kim, Hee Sung, Oshima, Akira, Michalowski, Aleksandra, Green, Jeffrey E.·2011·PLoS ONE
DOI 10.1371/journal.pone.0016694PMC PMC3041770
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Abstract

BACKGROUND: We initiated a prospective trial to identify transcriptional alterations associated with acquired chemotherapy resistance from pre- and post-biopsy samples from the same patient and uncover potential molecular pathways involved in treatment failure to help guide therapeutic alternatives. METHODOLOGY/PRINCIPAL FINDINGS: A prospective, high-throughput transcriptional profiling study was performed using endoscopic biopsy samples from 123 metastatic gastric cancer patients prior to cisplatin and fluorouracil (CF) combination chemotherapy. 22 patients who initially responded to CF were re-biopsied after they developed resistance to CF. An acquired chemotherapy resistance signature was identified by analyzing the gene expression profiles from the matched pre- and post-CF treated samples. The acquired resistance signature was able to segregate a separate cohort of 101 newly-diagnosed gastric cancer patients according to the time to progression after CF. Hierarchical clustering using a 633-gene acquired resistance signature (feature selection at P<0.01) separated the 101 pretreatment patient samples into two groups with significantly different times to progression (2.5 vs. 4.7 months). This 633-gene signature included the upregulation of AKT1, EIF4B, and RPS6 (mTOR pathway), DNA repair and drug metabolism genes, and was enriched for genes overexpressed in embryonic stem cell signatures. A 72-gene acquired resistance signature (a subset of the 633 gene signature also identified in ES cell-related gene sets) was an independent predictor for time to progression (adjusted P = 0.011) and survival (adjusted P = 0.034) of these 101 patients. CONCLUSION/SIGNIFICANCE: This signature may offer new insights into identifying new targets and therapies required to overcome the acquired resistance of gastric cancer to CF.

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  • Prior work has assessed the utility of mutational and transcriptomic signatures in predicting response to cisplatin, but none of these advancements have been translated into routine clinical care.

    “Given its widespread use, it comes as no surprise that prior work has assessed the utility of mutational and transcriptomic signatures in predicting response to this drug; yet, to the best knowledge of these authors, none of these advancements have been translated into routine clinical care15–19.”

    From Exploiting convergent phenotypes to derive a pan-cancer cisplatin response gene expression signature (2023) · cites this paper as [17]

    The Results and Discussion describe a gene-expression signature associated with resistance to cisplatin–fluorouracil therapy in gastric cancer and its potential to predict response. Our copy does not establish that mutational signatures were assessed or that none of these approaches entered routine clinical care; the Discussion says only that earlier genomic predictors had mixed performance. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Kim, H. K., Choi, I. J., Kim, C. G., Kim, H. S., Oshima, A., Michalowski, A., & Green, J. E.
Affiliations
  • National Institutes of Health (US)
  • National Cancer Center (KR)
Corresponding author
Green, Jeffrey E.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-02-18
Volume
6
Issue
2
Pages
e16694
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0016694
PMC
PMC3041770
OpenAlex
W2009326542
Cited by
135
References
0
Citations by year
2026: 3 · 2025: 5 · 2024: 8 · 2023: 11 · 2022: 14 · 2021: 11 · 2020: 6 · 2019: 9 · 2018: 5 · 2017: 14 · 2016: 10 · 2015: 7 · 2014: 11 · 2013: 8 · 2012: 11
FWCI
8.72
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Ministry of Education, Science and Technology (2010K001121)
  • National Institutes of Health
  • National Cancer Institute
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Keywords
gastric cancer, cisplatin, 5-fluorouracil, gene expression signatures, metastatic gastric cancer, mTOR signaling, AKT1, eIF4B, ribosomal protein S6, DNA repair genes, drug metabolism genes, time to progression, survival prediction, endoscopic biopsy
MeSH terms
Adenocarcinoma, Antineoplastic Combined Chemotherapy Protocols, Cisplatin, Female, Fluorouracil, Humans, Male, Middle Aged, Neoplasm Metastasis, Stomach Neoplasms, Gene Expression Regulation, Neoplastic, Cluster Analysis, Drug Resistance, Neoplasm, Gene Expression Profiling, High-Throughput Screening Assays

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