Clinical potential of SKP2 as diagnostic marker and therapeutic target in small cell lung cancer

IF 2.4 Q2 RESPIRATORY SYSTEM Respiratory investigation Pub Date : 2024-08-07 DOI:10.1016/j.resinv.2024.07.014
Naohisa Matsumoto , Ken Tajima , Fumiyuki Takahashi , Yoichiro Mitsuishi , Aditya Wirawan , Moulid Hidayat , Wira Winardi , Adityo Wibowo , Daisuke Hayakawa , Kenta Izumi , Koichiro Kanamori , Yosuke Miyashita , Takafumi Handa , Tetsuhiko Asao , Ryo Ko , Takehito Shukuya , Naoko Shimada , Kazuya Takamochi , Takuo Hayashi , Kenji Suzuki , Kazuhisa Takahashi
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Abstract

Background

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.

Methods

We analyzed a genome-wide loss-of-function screening database to identify vulnerabilities in SCLC for the development of urgently needed novel therapies.

Results

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 SCFSKP2 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.

Conclusion

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.

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SKP2 作为小细胞肺癌诊断标志物和治疗靶点的临床潜力。
背景:小细胞肺癌(SCLC小细胞肺癌(SCLC)是侵袭性最强的肺癌类型。在过去的几十年中,由于超过 15 年未取得重大治疗突破,总生存率一直没有明显改善:方法:我们分析了一个全基因组功能缺失筛选数据库,以确定SCLC中的薄弱环节,从而开发出急需的新型疗法:结果:我们发现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)依次是SCLC中最重要的两个基因。值得注意的是,SKP2 和 CKS1B 构成了 E3 泛素连接酶 SCFSKP2 复合物的 p27 结合袋。组织芯片上的免疫组化显示,SKP2在95%以上的样本中都有表达,其表达水平远远高于常用的神经内分泌标志物。不出所料,SCLC 细胞系对 SKP2 抑制很敏感。此外,SKP2或CKS1B敲除诱导RB1突变细胞凋亡,而诱导RB1野生型细胞衰老:尽管SKP2敲除诱导生长抑制的机制在RB1野生型和突变型SCLC中有所不同,但无论RB1突变状态如何,SKP2都可被视为SCLC患者的新型治疗靶点。我们的研究结果表明,SKP2 是一种潜在的新型 SCLC 临床诊断标志物和治疗靶点。
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来源期刊
Respiratory investigation
Respiratory investigation RESPIRATORY SYSTEM-
CiteScore
4.90
自引率
6.50%
发文量
114
审稿时长
64 days
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