美国加州大学旧金山分校E. Alejandro Sweet-Cordero和斯坦福大学Jennifer R. Cochran研究组合作，发现一种针对肺腺癌CLCF1-CNTFR信号的工程诱饵受体的抗肿瘤活性。2019年11月7日，《自然—医学》在线发表了这项成果。

他们验证了肺腺癌（LUAD）中心肌营养因子样细胞因子1（CLCF1）-睫状神经营养因子受体（CNTFR）信号轴的功能意义，并产生了隔离CLCF1的高亲和力可溶性受体（eCNTFR-Fc），从而抑制其致癌作用。在致癌性Kras激活和Trp53缺失的驱动下，eCNTFR–Fc在多种异种移植模型和自发模型中，LUAD的高度侵袭性基因工程小鼠模型中均抑制肿瘤的生长。通过eCNTFR–Fc清除CLCF1在由致癌性KRAS驱动的肿瘤中似乎最有效。他们观察到eCNTFR-Fc的有效性与保留了水解三磷酸鸟苷的内在能力的KRAS突变之间的相关性，这表明其作用机理可能与三磷酸鸟苷的负载有关。总体而言，他们将CLCF1-CNTFR信号的阻断作用命名为一种新治疗机会，其主要针对于LUAD和可能在肿瘤微环境中存在CLCF1的其他肿瘤类型。

据介绍，肿瘤微环境中的促炎细胞因子可以促进肿瘤生长，但其作为治疗靶标的价值仍未得到充分利用。

附：英文原文

Title: Antitumor activity of an engineered decoy receptor targeting CLCF1–CNTFR signaling in lung adenocarcinoma

Author: Jun W. Kim, Cesar P. Marquez, Kaja Kostyrko, Amanda L. Koehne, Kieren Marini, David R. Simpson, Alex G. Lee, Stanley G. Leung, Leanne C. Sayles, Joseph Shrager, Irene Ferrer, Luis Paz-Ares, Melanie Hayden Gephart, Silvestre Vicent, Jennifer R. Cochran, E. Alejandro Sweet-Cordero

Issue&Volume: 2019-11-07

Abstract: Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFRFc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFRFc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFRFc appears most effective in tumors driven by oncogenic KRAS. We observed a correlation between the effectiveness of eCNTFRFc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate, suggesting that the mechanism of action may be related to altered guanosine triphosphate loading. Overall, we nominate blockade of CLCF1CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment. A first-in-class engineered receptor decoy that neutralizes CLCF1CNTFR signaling exhibits antitumor activity in preclinical models of lung adenocarcinoma driven by some mutant KRAS variants and other oncogenic genotypes.

DOI: 10.1038/s41591-019-0612-2

Source:https://www.nature.com/articles/s41591-019-0612-2