西班牙国家肿瘤研究中心脑转移组Manuel Valiente研究组提出，基于可操作的S100A9/RAGE抵抗机制的放射敏感脑转移分层。2022年4月11日在《自然—医学》杂志发表了该论文。

鉴于患者可用的治疗选择有限，且对转移性病变对全脑放疗（WBRT）耐药的分子机制了解不足，他们试图发现有助于改进患者选择的可操作靶点和生物标记物。通过对WBRT耐受性脑转移的实验性体内模型进行无偏分析，他们确定脑转移中S100A9–RAGE–NF-κB–JunB通路的激活是该器官抵抗的潜在介质。从遗传学或药理学上靶向该途径足以逆转WBRT耐药性，并在低剂量辐射下增加体内治疗效益。在原发性黑色素瘤、肺腺癌或乳腺癌发生脑转移的患者中，脑损伤中内源性S100A9水平与WBRT的临床反应相关，并强调了血液中S100A9水平作为无创生物标记物的潜力。

总的来说，他们提供了一个分子框架来个性化WBRT，并通过与平衡治疗效益和毒性的放射增敏剂相结合来提高其疗效。

研究人员表示，WBRT是许多脑转移患者的治疗支柱；然而，它在预防疾病进展和相关毒性方面的功效对这种方法的临床影响提出了质疑，并强调了替代治疗的必要性。

附：英文原文

Title: Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Author: Monteiro, Ctia, Miarka, Lauritz, Perea-Garca, Mara, Priego, Neibla, Garca-Gmez, Pedro, lvaro-Espinosa, Laura, de Pablos-Aragoneses, Ana, Yebra, Natalia, Retana, Diana, Baena, Patricia, Fustero-Torre, Coral, Graa-Castro, Osvaldo, Troul, Kevin, Caleiras, Eduardo, Tezanos, Patricia, Muela, Pablo, Cintado, Elisa, Trejo, Jos Luis, Seplveda, Juan Manuel, Gonzlez-Len, Pedro, Jimnez-Roldn, Luis, Moreno, Luis Miguel, Esteban, Olga, Prez-Nez, ngel, Hernndez-Lain, Aurelio, Mazarico Gallego, Jos, Ferrer, Irene, Surez, Roco, Garrido-Martn, Eva M., Paz-Ares, Luis, Dalmasso, Celine, Cohen-Jonathan Moyal, Elizabeth, Siegfried, Aurore, Hegarty, Aisling, Keelan, Stephen, Varelija, Damir, Young, Leonie S., Mohme, Malte, Goy, Yvonne, Wikman, Harriet, Fernndez-Aln, Jose, Blasco, Guillermo, Alczar, Luca, Cabauz, Clara, Grivennikov, Sergei I., Ianus, Andrada, Shemesh, Noam, Faria, Claudia C., Lee, Rebecca, Lorigan, Paul, Le Rhun, Emilie, Weller, Michael, Soffietti, Riccardo, Bertero, Luca, Ricardi, Umberto, Bosch-Barrera, Joaquim, Sais, Elia, Teixidor, Eduard, Hernndez-Martnez, Alejandro, Calvo, Alfonso, Aristu, Javier, Martin, Santiago M., Gonzalez, Alvaro, Adler, Omer, Erez, Neta, Valiente, Manuel

Issue&Volume: 2022-04-11

Abstract: Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.

DOI: 10.1038/s41591-022-01749-8

Source: https://www.nature.com/articles/s41591-022-01749-8