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

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 SCF ^SKP2 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.
Competing Interests: Declaration of competing interest Ken Tajima received research funding from Novartis. Kazuhisa Takahashi received research funding from Chugai Pharm, MSD, Ono Pharm, and Bristol-Myers Squibb. Additionally, Kazuhisa Takahashi acknowledges donations from Eli Lilly Japan, Teijin Pharm, Chugai Pharm, Nippon Boehringer Ingelheim, Kyorin Pharm, Taiho Pharm, and Sanofi. The other authors have no conflicts of interest.
(Copyright © 2024 [The Author]. Published by Elsevier B.V. All rights reserved.)