摘要
背景:肺癌占全世界五分之一的癌症死亡人数,并且编码Kirsten大鼠肉瘤(KRAS)癌蛋白的基因突变定义了非小细胞肺癌(NSCLC)的最大分子亚群。这些肿瘤的特征在于激活的MAPK信号传导,然而,KRAS突变或下游信号分子的靶向抑制剂尚未被批准用于常规临床使用。 目的:本评价的主要目的是批判性地总结MEK和ERK抑制剂在KRAS突变型肺癌的临床前模型和人类临床试验中的当前发展状态,特别是根据新出现的免疫检查点封锁的概念。 方法:我们进行了基于Pubmed的文献检索,并考虑了基础和翻译生物医学和生物化学研究以及过去和正在进行的人类临床试验(www.clinicaltrials.gov)等领域的出版物。 结果和结论:MAPK通路靶向剂在临床前模型中是有效的,但由于缺乏预测因子,毒性和肿瘤内适应性动态激酶重编程,其对KRAS突变NSCLC患者的益处有限。总体而言,与ERK抑制剂相比,MEK抑制剂在临床开发中进一步发展。新的治疗策略如免疫检查点封锁目前正在革新治疗范例,未来的临床试验需要显示它们是否取代MAPK靶向策略或作为附加药物使用。
关键词: KRAS,非小细胞肺癌,MEK和ERK抑制剂,GEMM,临床试验,免疫检查点封锁。
Current Medicinal Chemistry
Title:Back to the Bench? MEK and ERK Inhibitors for the Treatment of KRAS Mutant Lung Adenocarcinoma
Volume: 25 Issue: 5
关键词: KRAS,非小细胞肺癌,MEK和ERK抑制剂,GEMM,临床试验,免疫检查点封锁。
摘要: Background: Lung cancer accounts for one in five cancer deaths worldwide and mutations in the gene encoding for the Kirsten rat sarcoma (KRAS) oncoprotein define the largest molecular subset of non-small cell lung cancer (NSCLC). These tumors are characterized by activated MAPK signaling, however, no targeted inhibitors of mutant KRAS or of downstream signaling molecules have yet been approved for routine clinical use.
Objective: The primary objective of this review is to critically summarize the current developmental state of MEK and ERK inhibitors in pre-clinical models and in human clinical trials for KRAS mutant lung cancer particularly in light of the newly emerging concept of immune checkpoint blockade.
Method: We performed a Pubmed-based literature search and considered publications from the fields of basic and translational biomedicinal and biochemistry research, as well as from past and ongoing human clinical trials (www.clinicaltrials.gov).
Results and Conclusions: MAPK pathway targeting agents are efficacious in pre-clinical models but their benefit is limited for patients with KRAS mutant NSCLC due to the lack of predictive factors, toxicity and the adaptive dynamic kinome reprogramming within the tumor. Overall, MEK inhibitors have advanced further in clinical development compared to ERK inhibitors. New treatment strategies as e.g. immune checkpoint blockade are currently revolutionizing the treatment paradigms and future clinical trials need to show if they replace MAPK targeting strategies or are used as add-on.
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Cite this article as:
Back to the Bench? MEK and ERK Inhibitors for the Treatment of KRAS Mutant Lung Adenocarcinoma, Current Medicinal Chemistry 2018; 25 (5) . https://dx.doi.org/10.2174/0929867324666170530093100
DOI https://dx.doi.org/10.2174/0929867324666170530093100 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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