Differentially Expressed Genes and Signaling Pathways Potentially Involved in Primary Resistance to Chemo-Immunotherapy in Advanced-Stage Gastric Cancer Patients

Mauricio P. Pinto, Matías Muñoz-Medel, Ignacio N. Retamal, Maria Loreto Bravo, Verónica Latapiat, Miguel Córdova-Delgado, Charlotte N. Hill, M. Fernanda Fernández, Carolina Sánchez, Mauricio A. Sáez, Alberto J.M. Martin, Sebastián Morales-Pison, Ricardo Fernandez-Ramires, Benjamín García-Bloj, Gareth I. Owen, Marcelo Garrido

Research output: Contribution to journalArticlepeer-review

Abstract

Recently, the combination of chemotherapy plus nivolumab (chemo-immunotherapy) has become the standard of care for advanced-stage gastric cancer (GC) patients. However, despite its efficacy, up to 40% of patients do not respond to these treatments. Our study sought to identify variations in gene expression associated with primary resistance to chemo-immunotherapy. Diagnostic endoscopic biopsies were retrospectively obtained from advanced GC patients previously categorized as responders (R) or non-responders (NR). Thirty-four tumor biopsies (R: n = 16, NR: n = 18) were analyzed by 3' massive analysis of cDNA ends (3'MACE). We found >30 differentially expressed genes between R and NRs. Subsequent pathway enrichment analyses demonstrated that angiogenesis and the Wnt-β-catenin signaling pathway were enriched in NRs. Concomitantly, we performed next generation sequencing (NGS) analyses in a subset of four NR patients that confirmed alterations in genes that belonged to the Wnt/β-catenin and the phosphoinositide 3-kinase (PI3K) pathways. We speculate that angiogenesis, the Wnt, and the PI3K pathways might offer actionable targets. We also discuss therapeutic alternatives for chemo-immunotherapy-resistant advanced-stage GC patients.

Original languageEnglish
JournalInternational Journal of Molecular Sciences
Volume24
Issue number1
DOIs
StatePublished - 20 Dec 2022
Externally publishedYes

Keywords

  • angiogenesis
  • cancer therapy
  • gastric cancer
  • immunotherapy resistance
  • molecular oncology
  • PI3K pathway
  • Wnt pathway
  • β-catenin

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