第三代EGFR和ALK抑制剂:耐药机制和管理

2022-05-29 10:57

在非小细胞肺癌(NSCLC)中，EGFR突变和ALK重排作为可操作的致癌驱动因子的发现，推动了一种生物标志物导向的晚期疾病治疗模式。

SCI

28 MAy 2022

Third- generation EGFR and ALK inhibitors: mechanisms of resistance and management

（Nat Rev Clin Oncol；IF：66.675）

Correspondence to：Department of Medicine, Massachusetts General Hospital Cancer Center,Boston, MA, USA.e- mail: jjlin1@partners.org
Cooper AJ, Sequist LV, Lin JJ. Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management. Nat Rev Clin Oncol 2022. DOI: 10.1038/s41571-022-00639-9

Abstract 摘要

The discoveries of EGFR mutations and ALK rearrangements as actionable oncogenic drivers in non- small- cell lung cancer (NSCLC) has propelled a biomarker- directed treatment paradigm for patients with advanced- stage disease. Numerous EGFR and ALK tyrosine kinase inhibitors (TKIs) with demonstrated efficacy in patients with EGFR- mutant and ALK- rearranged NSCLCs have been developed, culminating in the availability of the highly effective thirdgeneration TKIs osimertinib and lorlatinib, respectively. Despite their marked efficacy, resistance to these agents remains an unsolved fundamental challenge. Both ‘on- target’ mechanisms (largely mediated by acquired resistance mutations in the kinase domains of EGFR or ALK) and ‘off- target’ mechanisms of resistance (mediated by non- target kinase alterations such as bypass signalling activation or phenotypic transformation) have been identified in patients with disease progression on osimertinib or lorlatinib. A growing understanding of the biology and spectrum of these mechanisms of resistance has already begun to inform the development of more effective therapeutic strategies. In this /Review, we discuss the development of third- generation EGFR and ALK inhibitors, predominant mechanisms of resistance, and approaches to tackling resistance in the clinic, ranging from novel fourth- generation TKIs to combination regimens and other investigational therapies.

在非小细胞肺癌(NSCLC)中，EGFR突变和ALK重排作为可操作的致癌驱动因子的发现，推动了一种生物标志物导向的晚期疾病治疗模式。许多EGFR和ALK酪氨酸激酶抑制剂(TKIs)已被开发出来，在EGFR突变和ALK重排的NSCLC患者中显示出疗效，高效的第三代TKIs分别为奥西替尼和劳拉替尼·。尽管它们有显著的功效，但对这些药物的耐药性仍然是一个尚未解决的根本性挑战。靶向机制(很大程度上由获得性耐药突变激酶域的EGFR或ALK)和耐药机制 (由非靶向激酶改变如旁路信号激活或表型转换)已在使用奥希替尼或劳拉替尼的疾病进展的患者中明确。对这些耐药的生物学机制日益了解已经开始为开发更有效的治疗策略提供信息。在这篇综述中，我们讨论了第三代EGFR和ALK抑制剂的发展，主要的耐药机制，以及在临床中解决耐药的方法，讨论了从新的第四代TKIs到联合方案和其他研究性治疗。