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

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.

Exploring the current landscape of single‐cell RNA sequencing applications in gastric cancer research

“…Additionally, scRNA-seq reveals distinct cell subpopulations associated with tumour characteristics and dysregulated signalling pathways. 4 Moreover, it investigates the tumour microenvironment (TME) and its interactions with immune cells, furnishing valuable information for the development of immunotherapeutic targets. 5 Despite the advancements in scRNA-seq, challenges persist in its application to GC, primarily due to the high tumour heterogeneity and technical limitations.…”

“…To confront the heterogeneity and aggressiveness of GC, the emergence of single‐cell ribonucleic acid sequencing (scRNA‐seq) has introduced promising technology for profiling gene expression at the individual cell level 3–5 . This transformative technique has revolutionized transcriptome analysis by providing unprecedented precision and depth, enabling a comprehensive understanding of cellular diversity within complex gastric tumour tissues.…”

“…2 To confront the heterogeneity and aggressiveness of GC, the emergence of single-cell ribonucleic acid sequencing (scRNA-seq) has introduced promising technology for profiling gene expression at the individual cell level. [3][4][5] This transformative technique has revolutionized transcriptome analysis by providing unprecedented precision and depth, enabling a comprehensive understanding of cellular diversity within complex gastric tumour tissues. Through its capacity to unravel cellular heterogeneity, gene expression dynamics and intercellular interactions, scRNA-seq has shed light on intricate biological processes, including cancer development and progression.…”

“…It provides insights into the heterogeneity of GC and aids in the identification of potential therapeutic targets. Additionally, scRNA‐seq reveals distinct cell subpopulations associated with tumour characteristics and dysregulated signalling pathways 4 . Moreover, it investigates the tumour microenvironment (TME) and its interactions with immune cells, furnishing valuable information for the development of immunotherapeutic targets 5 …”