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, MariaLoreto Bravo, Verónica Latapiat, Miguel Córdova‐Delgado, Charlotte Hill, M. Fernanda Fernández, Carolina Sánchez‐Rodríguez, Mauricio Sáez, Alberto J. M. Martín, Sebastián Morales, Ricardo Fernández‐Ramires, Benjamín García‐Bloj, Gareth I. Owen, Marcelo Garrido
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.