Rocca Andrea, Crinò Lucio, Braga Luca, Salton Francesco, Ruaro Barbara, Confalonieri Marco, Generali Daniele, Confalonieri Paola
Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Meldola, Italy.
Br J Cancer. 2025 Aug 23. doi: 10.1038/s41416-025-03139-6.
Non-small cell lung cancer (NSCLC) represents a heterogeneous group of malignancies characterised by diverse histological and molecular features. Some NSCLCs, particularly adenocarcinomas, harbour genomic alterations in receptor tyrosine kinases or downstream RAS/RAF signalling pathways, which are targets of effective therapies. NSCLCs lacking actionable genomic alterations often benefit from immune checkpoint inhibitors, though only a minority of patients achieve long-term survival. These tumours often carry alterations in tumour suppressor genes like TP53, KEAP1, STK11, or NF1, for which pharmacological strategies are still under investigation. This review explores emerging therapeutic opportunities unveiled by multi-omics studies in NSCLCs without actionable genomic alterations. Proteogenomic approaches-integrating genomic, transcriptomic and proteomic data-enable a comprehensive understanding of NSCLC molecular landscapes and signalling network dysregulation, helping to identify distinct tumour subtypes and potential therapeutic targets. These tumours exhibit alterations in cell cycle regulation, DNA repair, immune signalling, epigenetic modulation and metabolic and redox pathways. Although therapies targeting tumour suppressor genes like p53 remain highly anticipated, extending our understanding of the broader molecular landscape in these tumours may reveal novel vulnerabilities and inform the development of novel drugs or combination strategies. This could further advance precision oncology for NSCLC.
非小细胞肺癌（NSCLC）是一组异质性恶性肿瘤，具有多样的组织学和分子特征。一些NSCLC，尤其是腺癌，在受体酪氨酸激酶或下游RAS/RAF信号通路中存在基因组改变，这些是有效治疗的靶点。缺乏可操作基因组改变的NSCLC通常受益于免疫检查点抑制剂，尽管只有少数患者能实现长期生存。这些肿瘤通常携带肿瘤抑制基因如TP53、KEAP1、STK11或NF1的改变，针对这些基因的药理学策略仍在研究中。本综述探讨了多组学研究在缺乏可操作基因组改变的NSCLC中揭示的新兴治疗机会。蛋白质基因组学方法——整合基因组、转录组和蛋白质组数据——能够全面了解NSCLC的分子格局和信号网络失调，有助于识别不同的肿瘤亚型和潜在治疗靶点。这些肿瘤在细胞周期调控、DNA修复、免疫信号传导、表观遗传调控以及代谢和氧化还原途径中表现出改变。尽管针对p53等肿瘤抑制基因的疗法仍然备受期待，但扩展我们对这些肿瘤更广泛分子格局的理解可能会揭示新的脆弱性，并为新药开发或联合策略提供信息。这可能会进一步推动NSCLC的精准肿瘤学发展。
