Emerging Paradigms in the Development of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer
Emerging Paradigms in the Development of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer
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DOI：
10.1200/jco.2012.45.2029
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发表时间：
2013-11-01
影响因子：
45.3
通讯作者：
Shaw, Alice T.
中科院分区：
文献类型：
--
作者：
Gainor, Justin F.;Shaw, Alice T.
酪氨酸激酶抑制剂（TKI）在特定非小细胞肺癌（NSCLC）患者中的成功改变了疾病的管理，将新的重点放在了解肿瘤标本的分子特征上。现在认识到，表皮生长因子受体（EGFR）和间变性淋巴瘤激酶（ALK）的遗传改变定义了两种独特的NSCLC亚型，对基因型定向TKI高度应答。然而，尽管这种初始敏感性，这种疗法的长期有效性普遍受到耐药性发展的限制。确定这种耐药性背后的机制是一个正在进行深入研究的领域。在这篇综述中，我们提供了该领域的最新经验的概述，重点是临床前耐药模型和患者来源的TKI耐药肿瘤标本的研究结果。尽管在EGFR突变型和ALK阳性患者中已经确定了不同的TKI耐药机制，但我们强调了这些群体之间共有的耐药共同原则。这些包括激酶靶点的继发性突变的发展、主要癌基因的基因扩增和旁路信号传导束的上调。在EGFR突变患者和ALK阳性患者中，获得性耐药也可能是一个动态的多因素过程，可能需要使用联合治疗。我们认为，对EGFR突变或ALK重排患者中TKI耐药机制的深入了解可能会为NSCLC新型治疗策略的开发提供信息，这也可能推广到其他激酶驱动的恶性肿瘤。(C)2013年美国临床肿瘤学会
The success of tyrosine kinase inhibitors (TKIs) in select patients with non-small-cell lung cancer (NSCLC) has transformed management of the disease, placing new emphasis on understanding the molecular characteristics of tumor specimens. It is now recognized that genetic alterations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) define two unique subtypes of NSCLC that are highly responsive to genotype-directed TKIs. Despite this initial sensitivity, however, the long-term effectiveness of such therapies is universally limited by the development of resistance. Identifying the mechanisms underlying this resistance is an area of intense, ongoing investigation. In this review, we provide an overview of recent experience in the field, focusing on results from preclinical resistance models and studies of patient-derived, TKI-resistant tumor specimens. Although diverse TKI resistance mechanisms have been identified within EGFR-mutant and ALK-positive patients, we highlight common principles of resistance shared between these groups. These include the development of secondary mutations in the kinase target, gene amplification of the primary oncogene, and upregulation of bypass signaling tracts. In EGFR-mutant and ALK-positive patients alike, acquired resistance may also be a dynamic and multifactorial process that may necessitate the use of treatment combinations. We believe that insights into the mechanisms of TKI resistance in patients with EGFR mutations or ALK rearrangements may inform the development of novel treatment strategies in NSCLC, which may also be generalizable to other kinase-driven malignancies. (C) 2013 by American Society of Clinical Oncology