Department of Hematology and Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330032, Chile.
Masters' Program of Research in Health Sciences, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330077, Chile.
Int J Mol Sci. 2022 Dec 20;24(1):1. doi: 10.3390/ijms24010001.
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.
最近，化疗联合纳武利尤单抗（化疗免疫治疗）已成为晚期胃癌（GC）患者的标准治疗方法。然而，尽管这种治疗方法有效，但仍有高达 40%的患者对此类治疗无反应。我们的研究旨在确定与原发性化疗免疫治疗耐药相关的基因表达差异。我们回顾性地从先前被归类为应答者（R）或无应答者（NR）的晚期 GC 患者中获得诊断性内镜活检。对 34 个肿瘤活检（R：n=16，NR：n=18）进行了 3′端大规模 cDNA 末端分析（3′MACE）。我们发现 R 和 NR 之间有 >30 个差异表达基因。随后的通路富集分析表明，NR 中血管生成和 Wnt-β-catenin 信号通路富集。同时，我们对 4 名 NR 患者的部分患者进行了下一代测序（NGS）分析，证实了属于 Wnt/β-catenin 和磷酸肌醇 3-激酶（PI3K）通路的基因发生了改变。我们推测血管生成、Wnt 和 PI3K 通路可能提供可操作的靶点。我们还讨论了化疗免疫治疗耐药的晚期 GC 患者的治疗选择。
