Ernst Sophie M, Aldea Mihaela, von der Thüsen Jan H, de Langen Adrianus J, Smit Egbert F, Paats Marthe S, Aerts Joachim G J V, Mezquita Laura, Popat Sanjay, Besse Benjamin, Remon Jordi, Rolfo Christian, Dubbink Hendrikus J, Dingemans Anne-Marie C
Department of Respiratory Medicine, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands.
Department of Cancer Medicine, Gustave Roussy, Villejuif, France.
Nat Rev Clin Oncol. 2025 May;22(5):371-378. doi: 10.1038/s41571-025-01011-3. Epub 2025 Mar 14.
Advances in targeted therapies for patients with non-small-cell lung cancer have substantially improved the outcomes of those with actionable alterations in certain oncogenic driver genes. However, acquired resistance to these targeted therapies remains a major challenge. Understanding the mechanisms underlying acquired resistance will be crucial for the development of strategies that might either overcome this effect or delay the onset. Circulating tumour DNA, owing to the need for only minimally invasive sampling and a potential role as both a prognostic and predictive biomarker, is increasingly being used in both research and clinical practice. Several studies have explored the landscape of acquired resistance to targeted therapies using this approach. However, the methodologies of the published studies vary widely, and several major challenges remain in addressing the practical difficulties associated with these methods. These challenges currently limit the depth of research insight provided by the available data. In this Perspective, we review clinical reports describing the use of circulating tumour DNA to detect mechanisms of acquired resistance to targeted therapies, predominantly in patients with advanced-stage non-small-cell lung cancer, and highlight key unresolved questions with the aim of moving towards more-informative research studies.
非小细胞肺癌患者靶向治疗的进展显著改善了某些致癌驱动基因存在可操作改变患者的治疗结果。然而，对这些靶向治疗产生获得性耐药仍然是一个重大挑战。了解获得性耐药的潜在机制对于制定可能克服这种效应或延缓其发生的策略至关重要。循环肿瘤DNA由于只需进行微创采样，并且具有作为预后和预测生物标志物的潜在作用，越来越多地应用于研究和临床实践中。多项研究已使用这种方法探索了靶向治疗获得性耐药的情况。然而，已发表研究的方法差异很大，在解决与这些方法相关的实际困难方面仍存在几个重大挑战。这些挑战目前限制了现有数据所能提供的研究深度。在本观点文章中，我们回顾了描述使用循环肿瘤DNA检测靶向治疗获得性耐药机制的临床报告，主要针对晚期非小细胞肺癌患者，并突出了关键的未解决问题，旨在开展更具信息量的研究。
