文章：

了解和靶向NSCLC的耐药机制

Understanding and targeting resistance mechanisms in NSCLC

原文发布日期：2017-10-25

DOI: 10.1038/nrc.2017.84

类型: Review Article

开放获取: 否

要点：

1. The spectrum of known and putative oncogenic drivers with companion targeted therapies continues to increase. As broader mutational testing becomes more clinically available, a greater proportion of patients with non-small-cell lung cancer (NSCLC) will be eligible for targeted therapies.
2. Mechanisms of resistance to targeted therapies can be divided into 'on-target' alterations in the primary drug target and 'off-target' changes that influence downstream and parallel bypass signalling pathways.
3. There is both signalling crosstalk and overlap among downstream and bypass signalling pathways that lead to resistance to the different targeted therapies currently in clinical use for treating NSCLC, suggesting that common themes in the development of drug resistance can be leveraged to guide further development of therapeutic agents and strategies.
4. The upfront combination of therapies targeting both the oncogenic driver and common bypass pathways might delay the onset of disease progression in NSCLC and is the subject of ongoing clinical trials.
5. Bidirectional signalling between tumour cells and components of the tumour microenvironment (TME) shapes both the characteristics of the TME and the propensity of a tumour cell towards therapeutic resistance.
6. Tissue biopsy at disease progression might identify modes of therapeutic resistance to guide the rational selection of subsequent lines of therapy. Serial assessment of circulating tumour DNA might provide a complementary approach to capture heterogeneous and evolving resistance mechanisms in patients.

要点翻译：

1. 已知及潜在致癌驱动基因谱及其伴随的靶向治疗手段持续增加。随着更广泛的突变检测在临床上日益普及，将有更高比例的非小细胞肺癌（NSCLC）患者符合靶向治疗条件。
2. 靶向治疗耐药机制可分为原发性药物靶点的“靶内”改变，以及影响下游和旁路信号通路的“脱靶”变化。
3. 现有临床用于治疗NSCLC的不同靶向疗法所涉及的下游与旁路信号通路间既存在信号串扰，又存在功能重叠——这表明可利用耐药机制发展的共性规律来指导治疗药物与策略的后续开发。
4. 针对致癌驱动基因与常见旁路通路的前期联合治疗策略或可延缓NSCLC疾病进展，这一设想目前正处于临床试验验证阶段。
5. 肿瘤细胞与肿瘤微环境（TME）组分间的双向信号传导，共同塑造了TME特性并增强了肿瘤细胞的治疗耐药倾向。
6. 疾病进展期的组织活检可识别治疗耐药模式，从而指导后续治疗方案的合理选择。循环肿瘤DNA的连续监测则可为捕捉患者异质性及动态演变的耐药机制提供补充手段。

英文摘要：

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.

摘要翻译： 

在非小细胞肺癌（NSCLC）中，已确立和候选的致癌驱动突变谱不断扩大，加上越来越多针对这些驱动突变的信号转导通路抑制剂进入临床，这为改善患者预后带来了巨大机遇。尽管取得了这些分子层面的进展，晚期 NSCLC 仍因治疗耐药而基本无法治愈。在本综述中，我们讨论了靶基因自身改变（‘靶内’耐药）以及其他下游和平行通路改变（‘靶外’耐药）导致 NSCLC 靶向治疗耐药的机制，并概述了当前对肿瘤微环境双向互作如何促进治疗耐药的理解。我们重点指出 NSCLC 各亚型在靶向治疗耐药方面共有的机制主题，包括携带表皮生长因子受体（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/苏氨酸蛋白激酶 B-raf（BRAF）及其他尚未完全确立的癌蛋白致癌突变的亚型。最后，我们探讨如何基于这些机制主题指导治疗策略，包括联合治疗手段，以克服肿瘤异质性带来的挑战。

原文链接：

Understanding and targeting resistance mechanisms in NSCLC