肿瘤基因成瘾性非小细胞肺癌（NSCLC）中行动靶点的鉴定，推动了基于生物标志物的治疗策略，尤其是在晚期疾病中。尽管分子靶向治疗的成功是不可否认的，但其临床反应持续时间相对较短。虽然在基因水平上，出色的努力定义了肿瘤结构和克隆演化的复杂性，但对肿瘤在治疗过程中通过表型适应所参与的动态机制并没有给予相应的兴趣。在临床层面上，EGFR突变和ALK重排肿瘤的分子靶向治疗经常导致上皮向间充质转化（EMT）和原始腺癌的组织学转化，而不获取额外的遗传突变，从而限制了后续的治疗选择和患者的预后。在这里，我们提供了对控制这种现象的遗传和非遗传分子回路的当前理解的概述，介绍了当前的治疗策略和可能的创新治疗方法，以干预肺癌细胞的可塑性。版权所有©2023 Elsevier B.V.。保留所有权利。

The identification of actionable targets in oncogene-addicted non-small cell lung cancer (NSCLC) has fueled biomarker-directed strategies, especially in advanced stage disease. Despite the undeniable success of molecular targeted therapies, duration of clinical response is relatively short-lived. While extraordinary efforts have defined the complexity of tumor architecture and clonal evolution at the genetic level, not equal interest has been given to the dynamic mechanisms of phenotypic adaptation engaged by cancer during treatment. At the clinical level, molecular targeted therapy of EGFR-mutant and ALK-rearranged tumors often results in epithelial-to-mesenchymal transition (EMT) and histological transformation of the original adenocarcinoma without the acquisition of additional genetic lesions, thus limiting subsequent therapeutic options and patient outcome. Here we provide an overview of the current understanding of the genetic and non-genetic molecular circuits governing this phenomenon, presenting current strategies and potentially innovative therapeutic approaches to interfere with lung cancer cell plasticity.Copyright © 2023 Elsevier B.V. All rights reserved.