The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21231, USA.
Curr Oncol Rep. 2021 Feb 6;23(2):23. doi: 10.1007/s11912-020-01008-4.
Mitogen-activated protein kinase (MAPK) kinase (MEK) is an integral component of the RAS signaling pathway, one of the most frequently mutated pathways in cancer biology. MEK inhibitors were initially developed to directly target oncogenic signaling, but are recognized to have pleiotropic effects on both tumor cells and lymphocytes. Here, we review the preclinical and clinical evidence that MEK inhibition is immunomodulatory and discuss the potential rationale for combining MEK inhibitors with systemic immunotherapies.
MEK inhibition may modulate the tumor microenvironment (TME) through direct effects on both tumor cells and immune cells. Despite encouraging evidence that MEK inhibition can reprogram the tumor microenvironment (TME) and augment anti-tumor immunity regardless of KRAS/BRAF status, recent clinical outcome studies combining MEK inhibition with systemic immunotherapy have yielded mixed results. The combination of MEK inhibitors plus systemic immunotherapies has been tolerable, but has thus far failed to demonstrate clear evidence of synergistic clinical activity. These results underscore the need to understand the appropriate therapeutic context for this combination. MEK inhibitors have the potential to inhibit oncogenic signaling and reprogram the tumor immune microenvironment, representing an attractive therapy to combine with systemic immunotherapies. Ongoing preclinical and clinical studies will further clarify the immunomodulatory effects of MEK inhibitors to inform the design of rational therapeutic combinations.
综述目的：丝裂原活化蛋白激酶激酶（MEK）是 RAS 信号通路的一个组成部分，RAS 信号通路是癌症生物学中最常发生突变的途径之一。MEK 抑制剂最初是为了直接靶向致癌信号而开发的，但已被证实对肿瘤细胞和淋巴细胞都具有多效性作用。在这里，我们回顾了 MEK 抑制具有免疫调节作用的临床前和临床证据，并讨论了将 MEK 抑制剂与全身性免疫疗法联合应用的潜在合理依据。
最新发现：MEK 抑制可能通过直接作用于肿瘤细胞和免疫细胞来调节肿瘤微环境（TME）。尽管有令人鼓舞的证据表明，无论 KRAS/BRAF 状态如何，MEK 抑制都可以重新编程肿瘤微环境（TME）并增强抗肿瘤免疫，但最近将 MEK 抑制与全身性免疫疗法联合应用的临床结果研究得出的结果喜忧参半。MEK 抑制剂联合全身性免疫疗法具有良好的耐受性，但迄今为止未能证明具有明显的协同临床活性。这些结果强调了需要了解这种联合治疗的适当治疗环境。MEK 抑制剂具有抑制致癌信号和重新编程肿瘤免疫微环境的潜力，是与全身性免疫疗法联合应用的一种有吸引力的治疗方法。正在进行的临床前和临床研究将进一步阐明 MEK 抑制剂的免疫调节作用，为合理的治疗组合设计提供信息。
