Kim Chul, Giaccone Giuseppe
a Thoracic and Gastrointestinal Oncology Branch , National Cancer Institute, National Institutes of Health , Bethesda , MD , USA.
b Department of Oncology, Lombardi Comprehensive Cancer Center , Georgetown University , Washington , DC , USA.
Expert Opin Investig Drugs. 2018 Jan;27(1):17-30. doi: 10.1080/13543784.2018.1415324. Epub 2017 Dec 13.
The mitogen-activated protein kinase (MAPK) pathway is intimately implicated in the molecular pathogenesis of non-small-cell lung cancer (NSCLC). Aberrant MAPK signaling resulting from the upstream activating mutations converges on mitogen-activated protein kinase kinase 1/2 (MEK1/2), making MEK inhibition an attractive strategy for the treatment of NSCLC. Several MEK inhibitors have demonstrated anticancer activity in patients with NSCLC.
In this article, we discuss the biological rationale for the use of MEK inhibitors and summarize the clinical experience with MEK1/2 inhibitors for the treatment of NSCLC, from initial phase I studies to phase II/III studies, both as monotherapy or in combination with other anticancer agents.
Trametinib in combination with the BRAF inhibitor dabrafenib represents the first MEK1/2 inhibitor containing regimen that is approved for advanced BRAF-mutant NSCLC. Other MEK1/2 inhibitors that are also in advanced stages of clinical development include selumetinib, cobimetinib, and binimetinib. Several studies of MEK inhibitor combination therapies are underway, including trials using combined MEK inhibition and immune checkpoint blockade. Further research aimed at discovering biomarkers of response and resistance to MEK1/2 inhibitors will be needed to develop rational combination strategies for the treatment of NSCLC driven by aberrant MAPK signaling.
丝裂原活化蛋白激酶（MAPK）通路与非小细胞肺癌（NSCLC）的分子发病机制密切相关。上游激活突变导致的异常MAPK信号传导汇聚于丝裂原活化蛋白激酶激酶1/2（MEK1/2），使得MEK抑制成为治疗NSCLC的一种有吸引力的策略。几种MEK抑制剂已在NSCLC患者中显示出抗癌活性。
在本文中，我们讨论了使用MEK抑制剂的生物学原理，并总结了MEK1/2抑制剂治疗NSCLC的临床经验，从最初的I期研究到II/III期研究，包括单药治疗或与其他抗癌药物联合使用。
曲美替尼与BRAF抑制剂达拉非尼联合使用，代表了首个被批准用于晚期BRAF突变NSCLC的含MEK1/2抑制剂方案。其他也处于临床开发后期的MEK1/2抑制剂包括司美替尼、考比替尼和比美替尼。多项MEK抑制剂联合疗法的研究正在进行中，包括使用联合MEK抑制和免疫检查点阻断的试验。需要进一步研究以发现对MEK1/2抑制剂反应和耐药的生物标志物，从而制定合理的联合策略来治疗由异常MAPK信号传导驱动的NSCLC。
