塞利尼索是一种新型默克尔细胞癌 DNA 损伤反应抑制剂。

Selinexor is a novel inhibitor of DNA damage response in Merkel cell carcinoma.

机构信息

Department of Dermatology, The University of Texas McGovern Medical School, Houston, TX, USA.

Rice University, Houston, TX, USA.

出版信息

Clin Exp Dermatol. 2022 Jul;47(7):1354-1357. doi: 10.1111/ced.15120. Epub 2022 Mar 16.

DOI:10.1111/ced.15120

PMID:35120268

Abstract

Merkel cell carcinoma (MCC) is a highly lethal cutaneous carcinoma, which in ~80% of cases in the USA is aetiologically linked to Merkel cell polyomavirus (MCPyV). Immune checkpoint inhibitors (ICIs) can successfully treat ~50% of patients with metastatic MCC, but some MCCs are refractory to ICIs, possibly due to altered DNA damage response (DDR). Selinexor, an anticancer therapy that is currently approved in combination with chemotherapy for multiple myeloma, downregulates the small T and large T tumour antigens in MCC through selective inhibition of nuclear exportin 1 (XPO1). We examined the effect of varying doses of selinexor on DDR protein expression in MCPyV-positive and MCPyV-negative MCC cells. Selinexor was found to inhibit DDR protein expression in both MCPyV-positive and MCPyV-negative cells. Addition of selinexor alone or combined with ICI may be a promising treatment for MCC, but further in vivo research and clinical trials are required to validate these findings.

摘要

默克尔细胞癌（Merkel cell carcinoma，MCC）是一种高度致命的皮肤癌，在美国约 80%的病例与默克尔细胞多瘤病毒（Merkel cell polyomavirus，MCPyV）有关。免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）可成功治疗约 50%的转移性 MCC 患者，但部分 MCC 对 ICI 具有抗性，这可能与 DNA 损伤反应（DNA damage response，DDR）改变有关。Selinexor 是一种抗癌疗法，目前已获准与化疗联合用于多发性骨髓瘤的治疗，它通过选择性抑制核输出蛋白 1（nuclear exportin 1，XPO1）下调 MCC 中的小 T 和大 T 肿瘤抗原。我们研究了不同剂量的 Selinexor 对 MCPyV 阳性和 MCPyV 阴性 MCC 细胞 DDR 蛋白表达的影响。结果发现 Selinexor 可抑制 MCPyV 阳性和 MCPyV 阴性细胞的 DDR 蛋白表达。Selinexor 单独或与 ICI 联合使用可能是治疗 MCC 的一种有前途的方法，但需要进一步的体内研究和临床试验来验证这些发现。