The expanding spectrum of both established and candidate oncogenic driver mutations identified in non-small-cell lung cancer (NSCLC), coupled with the increasing number of clinically available signal transduction pathway inhibitors targeting these driver mutations, offers a tremendous opportunity to enhance patient outcomes. Despite these molecular advances, advanced-stage NSCLC remains largely incurable due to therapeutic resistance. In this Review, we discuss alterations in the targeted oncogene ('on-target' resistance) and in other downstream and parallel pathways ('off-target' resistance) leading to resistance to targeted therapies in NSCLC, and we provide an overview of the current understanding of the bidirectional interactions with the tumour microenvironment that promote therapeutic resistance. We highlight common mechanistic themes underpinning resistance to targeted therapies that are shared by NSCLC subtypes, including those with oncogenic alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1 proto-oncogene receptor tyrosine kinase (ROS1), serine/threonine-protein kinase b-raf (BRAF) and other less established oncoproteins. Finally, we discuss how understanding these themes can inform therapeutic strategies, including combination therapy approaches, and overcome the challenge of tumour heterogeneity.

中文翻译：

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了解和靶向NSCLC中的耐药机制

在非小细胞肺癌（NSCLC）中确定的既定和候选致癌驱动子突变的范围不断扩大，再加上针对这些驱动子突变的临床可用信号转导途径抑制剂的数量不断增加，为增强患者预后提供了巨大的机会。尽管取得了这些分子方面的进展，但由于治疗耐药性，晚期NSCLC仍在很大程度上无法治愈。在本综述中，我们讨论了靶向致癌基因（“未靶向”耐药性）以及其他下游和平行途径（“脱靶”耐药性）的改变，这些改变会导致对NSCLC靶向治疗的耐药性，并且我们将概述目前对促进治疗耐药性的肿瘤微环境双向相互作用的了解。我们重点介绍了对非小细胞肺癌亚型共有的靶向治疗有抵抗力的常见机制主题，包括那些在表皮生长因子受体（EGFR），间变性淋巴瘤激酶（ALK），ROS1原癌基因受体酪氨酸激酶（ROS1），丝氨酸具有致癌性改变的患者/苏氨酸蛋白激酶b-raf（BRAF）和其他较不成熟的癌蛋白。最后，我们讨论了如何理解这些主题可以为治疗策略（包括联合治疗方法）提供参考，并克服肿瘤异质性的挑战。丝氨酸/苏氨酸蛋白激酶b-raf（BRAF）和其他尚未确定的癌蛋白。最后，我们讨论了如何理解这些主题可以为治疗策略（包括联合治疗方法）提供参考，并克服肿瘤异质性的挑战。丝氨酸/苏氨酸蛋白激酶b-raf（BRAF）和其他尚未确定的癌蛋白。最后，我们讨论了如何理解这些主题可以为治疗策略（包括联合治疗方法）提供参考，并克服肿瘤异质性的挑战。