{"title":"Clinical potential of SKP2 as diagnostic marker and therapeutic target in small cell lung cancer","authors":"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","doi":"10.1016/j.resinv.2024.07.014","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>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.</p></div><div><h3>Methods</h3><p>We analyzed a genome-wide loss-of-function screening database to identify vulnerabilities in SCLC for the development of urgently needed novel therapies.</p></div><div><h3>Results</h3><p>We identified <em>SKP2</em> (encoding S-phase kinase-associated protein 2) and <em>CKS1B</em> (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<sup>SKP2</sup> 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 <em>RB1</em> mutant cells, whereas it induced senescence in <em>RB1</em> wild-type cells.</p></div><div><h3>Conclusion</h3><p>Although the mechanism underlying SKP2 knockdown-induced growth inhibition differs between <em>RB1</em>-wild-type and -mutant SCLC, SKP2 can be considered a novel therapeutic target for patients with SCLC regardless of the <em>RB1</em> mutation status. Our findings indicate that SKP2 is a potential novel clinical diagnostic marker and therapeutic target in SCLC.</p></div>","PeriodicalId":20934,"journal":{"name":"Respiratory investigation","volume":"62 5","pages":"Pages 901-909"},"PeriodicalIF":2.4000,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212534524001151/pdfft?md5=bd6f387b47310c081611aadf5fdfd15b&pid=1-s2.0-S2212534524001151-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Respiratory investigation","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2212534524001151","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"RESPIRATORY SYSTEM","Score":null,"Total":0}
引用次数: 0
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.