Avery Thomas Yul, Köhler Natalie, Zeiser Robert, Brummer Tilman, Ruess Dietrich Alexander
Department of General and Visceral Surgery, Center of Surgery, Medical Center University of Freiburg, Freiburg, Germany.
Department of Medicine I - Medical Center, Medical Center University of Freiburg, Freiburg, Germany.
Front Oncol. 2022 Jul 27;12:931774. doi: 10.3389/fonc.2022.931774. eCollection 2022.
Hyperactivation of the RAS-RAF-MEK-ERK cascade - a mitogen-activated protein kinase pathway - has a well-known association with oncogenesis of leading tumor entities, including non-small cell lung cancer, colorectal carcinoma, pancreatic ductal adenocarcinoma, and malignant melanoma. Increasing evidence shows that genetic alterations leading to RAS-RAF-MEK-ERK pathway hyperactivation mediate contact- and soluble-dependent crosstalk between tumor, tumor microenvironment (TME) and the immune system resulting in immune escape mechanisms and establishment of a tumor-sustaining environment. Consequently, pharmacological interruption of this pathway not only leads to tumor-cell intrinsic disruptive effects but also modification of the TME and anti-tumor immunomodulation. At the same time, the importance of ERK signaling in immune cell physiology and potentiation of anti-tumor immune responses through ERK signaling inhibition within immune cell subsets has received growing appreciation. Specifically, a strong case was made for targeted MEK inhibition due to promising associated immune cell intrinsic modulatory effects. However, the successful transition of therapeutic agents interrupting RAS-RAF-MEK-ERK hyperactivation is still being hampered by significant limitations regarding durable efficacy, therapy resistance and toxicity. We here collate and summarize the multifaceted role of RAS-RAF-MEK-ERK signaling in physiology and oncoimmunology and outline the rationale and concepts for exploitation of immunomodulatory properties of RAS-RAF-MEK-ERK inhibition while accentuating the role of MEK inhibition in combinatorial and intermittent anticancer therapy. Furthermore, we point out the extensive scientific efforts dedicated to overcoming the challenges encountered during the clinical transition of various therapeutic agents in the search for the most effective and safe patient- and tumor-tailored treatment approach.
RAS-RAF-MEK-ERK级联反应（一种丝裂原活化蛋白激酶途径）的过度激活与包括非小细胞肺癌、结直肠癌、胰腺导管腺癌和恶性黑色素瘤在内的主要肿瘤实体的肿瘤发生密切相关。越来越多的证据表明，导致RAS-RAF-MEK-ERK途径过度激活的基因改变介导了肿瘤、肿瘤微环境（TME）和免疫系统之间的接触依赖性和可溶性依赖性串扰，从而导致免疫逃逸机制并建立肿瘤维持环境。因此，该途径的药理学阻断不仅会导致肿瘤细胞内在的破坏作用，还会改变TME并进行抗肿瘤免疫调节。同时，ERK信号在免疫细胞生理学中的重要性以及通过抑制免疫细胞亚群内的ERK信号增强抗肿瘤免疫反应的作用越来越受到重视。具体而言，由于有前景的相关免疫细胞内在调节作用，靶向MEK抑制成为了一个有力的案例。然而，中断RAS-RAF-MEK-ERK过度激活的治疗药物的成功转化仍然受到持久疗效、治疗耐药性和毒性等重大限制的阻碍。我们在此整理并总结了RAS-RAF-MEK-ERK信号在生理学和肿瘤免疫中的多方面作用，并概述了利用RAS-RAF-MEK-ERK抑制的免疫调节特性的原理和概念，同时强调了MEK抑制在联合和间歇性抗癌治疗中的作用。此外，我们指出了为克服各种治疗药物临床转化过程中遇到的挑战而进行的广泛科学努力，以寻找最有效、最安全的针对患者和肿瘤的个体化治疗方法。
