RASON promotes KRASG12C-driven tumor progression and immune evasion in non-small cell lung cancer

作者：Jianzhuang Wu, Kexin Xie, Yixuan Zhang, Weiyi Zhang, Rongjie Cheng, Yaliang Zhang, Yugui Xia, Tongyan Liu, Rong Yin, Yudong Qiu, Tao Xu, Rutian Li, Qi Sun, Chao Yan · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2025 · DOI：10.1186/s13046-025-03369-9 · 被引用次数：9 · 研究领域：Monoclonal and Polyclonal Antibodies Research、Galectins and Cancer Biology、Glycosylation and Glycoproteins Research

Abstract Background KRAS is the most frequently mutated oncogene in human cancers, with KRAS G12C being a prevalent driver mutation in 12–13% non-small cell lung cancer (NSCLC) cases. Despite breakthroughs in KRAS G12C inhibitors such as sotorasib (AMG-510) and adagrasib (MRTX-849), clinical resistance remains a challenging issue, highlighting the need for deeper understanding of the molecular mechanisms underlying KRAS G12C -driven oncogenic signaling in NSCLC. Previously, we identified RASON as a novel regulator of KRAS G12D/V signaling in pancreatic cancer. Herein, we aim to explore the role of RASON in KRAS G12C -driven NSCLC and its therapeutic potential. Methods Immunohistochemistry analysis of NSCLC patient cohorts was performed to demonstrate the correlation between RASON expression and NSCLC progression. Immunoblotting was performed to evaluate the effects of RASON on KRAS G12C downstream signaling. In vitro and in vivo assays including cell proliferation, sphere formation, tumor implantation and genetic mouse models were performed to determine the oncogenic role of RASON. RNA-seq analysis was utilized to identify the key signaling pathway regulated by RASON. Immunofluorescence, immunoprecipitation, nuclear magnetic resonance and biochemistry assays were used to validate the interaction between KRAS G12C and RASON. Phagocytosis assay and flow cytometry were conducted to explore the effects of RASON on the tumor immune microenvironment. Pharmacological inhibition in s...