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. 2022 Dec 20;24(1):1.
doi: 10.3390/ijms24010001.

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

Mauricio P Pinto  1 , Matías Muñoz-Medel  2   3 , Ignacio N Retamal  4 , MariaLoreto Bravo  1 , Verónica Latapiat  5   6 , Miguel Córdova-Delgado  1 , Charlotte N Hill  1 , M Fernanda Fernández  4 , Carolina Sánchez  4 , Mauricio A Sáez  4 , Alberto J M Martin  6   7 , Sebastián Morales-Pison  4 , Ricardo Fernandez-Ramires  8 , Benjamín García-Bloj  4 , Gareth I Owen  9   10   11 , Marcelo Garrido  4
Affiliations

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

Mauricio P Pinto et al. Int J Mol Sci. .

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.

Keywords: PI3K pathway; Wnt pathway; angiogenesis; cancer therapy; gastric cancer; immunotherapy resistance; molecular oncology; β-catenin.

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Conflict of interest statement

Garrido (M.G.) has been a member of Scientific Advisory Boards during the past 36 months at Bayer, Novartis, MSD, BMS, Pfizer, Macrogenic, and Merck. MG has been an invited speaker in activities by Novartis, Pfizer, Bayer, BMS, MSD, GBT Biotoscana, and Lilly and has received traveling accommodation and attending support for international meetings by Novartis, MSD, and Bayer. G.I.O. has been an invited speaker on activities organized by Roche and has received traveling accommodations and attending support for international meetings by Roche and MSD. All other authors have no conflicts of interest to declare. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Differentially expressed genes in chemo-immunotherapy responders and non-responders by 3′ MACE. (a) Kaplan-Meier curve comparing survival rates between advanced GC patients categorized as responders (R) or non-responders (NR) to chemo-immunotherapy (LogRank, p = 0.018). (b) Unsupervised clustering of differentially expressed genes analyzed by 3′ massive analysis of cDNA ends (3′MACE). The lower panel shows clinical characteristics of patients (c) Waterfall plot of differentially expressed genes down-regulated or up-regulated in NR patients.
Figure 2
Figure 2
Enriched pathways in non-responders to chemo-immunotherapy. (a) Cell signaling pathway enrichment analyses were performed by obtaining gene lists of differentially expressed genes. (b) Diagram showing clinically relevant alterations in four chemo-immunotherapy NR advanced GC patients. Abbreviations: SNV: single nucleotide variant, INs: insertion, CNV: copy number variation.
Figure 3
Figure 3
Hypothetical model of chemo-immunotherapy-resistant tumors in advanced GC patient and potential therapeutic interventions. Briefly, aberrant high PI3K activity caused by PIK3CA/PIK3R1 mutations and/or PTEN loss increases Akt activation. In turn, activated Akt stimulates VEGF secretion and angiogenesis via mTOR. Additionally, Akt increases β-catenin activity and Wnt signaling via crosstalk with GSK3β. Increased Wnt signaling affects the tumor microenvironment (TME) via “immune exclusion”, increasing Treg survival and reducing CD8+T-cell proliferation, infiltration, and activation via a decrease in CCL4 in dendritic cells (DC). Highlighted potential therapeutic interventions include PI3K inhibitors such as Alpelisib, angiogenesis inhibitors such as bevacizumab or ramucirumab, and Wnt/β-catenin signaling inhibitors such as porcupine (PORCN) inhibitors, tankyrase inhibitors, or CBP/β-catenin antagonists.
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