TY - JOUR
T1 - Differentially Expressed Genes and Signaling Pathways Potentially Involved in Primary Resistance to Chemo-Immunotherapy in Advanced-Stage Gastric Cancer Patients
AU - Pinto, Mauricio P.
AU - Muñoz-Medel, Matías
AU - Retamal, Ignacio N.
AU - Bravo, Maria Loreto
AU - Latapiat, Verónica
AU - Córdova-Delgado, Miguel
AU - Hill, Charlotte N.
AU - Fernández, M. Fernanda
AU - Sánchez, Carolina
AU - Sáez, Mauricio A.
AU - Martin, Alberto J.M.
AU - Morales-Pison, Sebastián
AU - Fernandez-Ramires, Ricardo
AU - García-Bloj, Benjamín
AU - Owen, Gareth I.
AU - Garrido, Marcelo
N1 - Publisher Copyright:
© 2022 by the authors.
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - PI3K pathway
KW - Wnt pathway
KW - angiogenesis
KW - cancer therapy
KW - gastric cancer
KW - immunotherapy resistance
KW - molecular oncology
KW - β-catenin
UR - http://www.scopus.com/inward/record.url?scp=85145978931&partnerID=8YFLogxK
U2 - 10.3390/ijms24010001
DO - 10.3390/ijms24010001
M3 - Article
C2 - 36613445
AN - SCOPUS:85145978931
SN - 1661-6596
VL - 24
SP - 1
EP - 13
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 1
M1 - 1
ER -
