Schlafen 11 (SLFN11) 是一种 DNA/RNA 解旋酶，可调节细胞对复制应激的反应，并不可逆地触发复制阻断和细胞死亡。多项临床前体外研究和临床试验证实，SLFN11 表达可以预测接受 DNA 损伤化疗药物以及最近接受聚（ADP-核糖）聚合酶抑制剂治疗的晚期癌症患者的结果。 SLFN11 在许多癌症类型中的表达状态仍然未知，特别是在间叶性肿瘤中。本研究使用免疫组织化学方法评估了一组经过充分表征的 3808 个上皮肿瘤和 2850 个间充质和神经外胚层肿瘤的 SLFN11 表达。核 SLFN11 表达在一些最常见的癌症中很少见，例如肝细胞癌 (1%)、前列腺癌 (2%)、结直肠癌 (5%) 或乳腺癌 (16%)。相比之下，其他上皮肿瘤包括间皮瘤（92%）、透明细胞肾细胞癌（79%）、小细胞肺癌（76%）、扁桃体鳞状细胞癌（89%）和喉部鳞状细胞癌（71%），或卵巢浆液性癌 (69%) 大多为 SLFN11 阳性。与上皮性恶性肿瘤相比，SLFN11 在神经外胚层和间质肿瘤中的表达总体较高。大多数阳性实体包括促纤维增生性小圆细胞瘤（100%）、尤文肉瘤（92%）、未分化肉瘤（92%）、孤立性纤维瘤（91%）、去分化脂肪肉瘤（89%）、滑膜肉瘤（86%）、恶性周围神经鞘瘤（85%）。此外，这项研究还发现，由于缺乏 SLFN11 表达，肿瘤对 DNA 损伤药物（包括抗体药物缀合物）的反应可能更差。这些实体可能受益于替代治疗或克服 SLFN11 缺乏相关耐药性的策略。我们的方法和结果应作为未来生物标志物相关临床试验的基础。版权所有 © 2024 Wolters Kluwer Health, Inc. 保留所有权利。

Schlafen 11 (SLFN11), a DNA/RNA helicase, acts as a regulator of cellular response to replicative stress and irreversibly triggers replication block and cell death. Several preclinical in vitro studies and clinical trials established that SLFN11 expression predicts outcomes in patients with advanced cancer treated with DNA-damaging chemotherapeutics and more recently with poly(ADP-ribose) polymerase inhibitors. SLFN11 expression status remains unknown in many cancer types, especially in mesenchymal tumors. This study evaluated a cohort of well characterized 3808 epithelial and 2850 mesenchymal and neuroectodermal tumors for SLFN11 expression using immunohistochemistry. Nuclear SLFN11 expression was rare in some of the most common carcinomas, for example, hepatocellular (1%), prostatic (2%), colorectal (5%), or breast (16%) cancers. In contrast, other epithelial tumors including mesotheliomas (92%), clear cell renal cell carcinomas (79%), small cell lung cancers (76%), squamous cell carcinomas of the tonsil (89%) and larynx (71%), or ovarian serous carcinomas (69%) were mostly SLFN11-positive. Compared with epithelial malignancies, SLFN11 expression was overall higher in neuroectodermal and mesenchymal tumors. Most positive entities included desmoplastic small round cell tumor (100%), Ewing sarcoma (92%), undifferentiated sarcoma (92%), solitary fibrous tumor (91%), dedifferentiated liposarcoma (89%), synovial sarcoma (86%), and malignant peripheral nerve sheath tumor (85%). Also, this study identifies tumors with potentially worse response to DNA-damaging drugs including antibody drug conjugates due to the absence of SLFN11 expression. Such entities may benefit from alternative treatments or strategies to overcome SLFN11 deficiency-related drug resistance. Our approach and results should serve as a foundation for future biomarker-associated clinical trials.Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.