Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan.
Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan; Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan.
Respir Investig. 2024 Sep;62(5):901-909. doi: 10.1016/j.resinv.2024.07.014. Epub 2024 Aug 7.
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. The overall survival has not improved significantly over the last decades because no major therapeutic breakthroughs have been achieved for over 15 years.
We analyzed a genome-wide loss-of-function screening database to identify vulnerabilities in SCLC for the development of urgently needed novel therapies.
We identified SKP2 (encoding S-phase kinase-associated protein 2) and CKS1B (encoding CDC28 protein kinase regulatory subunit 1B) as the two most essential genes in that order in SCLC. Notably, SKP2 and CKS1B comprise the p27 binding pocket of the E3 ubiquitin ligase SCF complex. Immunohistochemistry on tissue microarrays revealed that SKP2 was expressed in >95% of samples at substantially higher levels than that observed for commonly used neuroendocrine markers. As expected, SCLC cell lines were sensitive to SKP2 inhibition. Furthermore, SKP2 or CKS1B knockdown induced apoptosis in RB1 mutant cells, whereas it induced senescence in RB1 wild-type cells.
Although the mechanism underlying SKP2 knockdown-induced growth inhibition differs between RB1-wild-type and -mutant SCLC, SKP2 can be considered a novel therapeutic target for patients with SCLC regardless of the RB1 mutation status. Our findings indicate that SKP2 is a potential novel clinical diagnostic marker and therapeutic target in SCLC.
小细胞肺癌（SCLC）是最具侵袭性的肺癌类型。尽管过去几十年没有取得重大治疗突破，但总体生存率并没有显著提高。
我们分析了全基因组功能丧失筛选数据库，以确定 SCLC 中的脆弱性，为急需的新型疗法的开发提供依据。
我们确定 SKP2（编码 S 期激酶相关蛋白 2）和 CKS1B（编码 CDC28 蛋白激酶调节亚基 1B）是 SCLC 中按此顺序排列的两个最关键基因。值得注意的是，SKP2 和 CKS1B 构成了 E3 泛素连接酶 SCF 复合物的 p27 结合口袋。组织微阵列的免疫组织化学显示，SKP2 在 >95%的样本中表达，其水平明显高于常用的神经内分泌标志物。正如预期的那样，SCLC 细胞系对 SKP2 抑制敏感。此外，SKP2 或 CKS1B 敲低可诱导 RB1 突变细胞凋亡，而诱导 RB1 野生型细胞衰老。
尽管 SKP2 敲低诱导生长抑制的机制在 RB1 野生型和突变型 SCLC 之间存在差异，但无论 RB1 突变状态如何，SKP2 均可被视为 SCLC 患者的一种新的治疗靶点。我们的研究结果表明，SKP2 是 SCLC 潜在的新型临床诊断标志物和治疗靶点。
