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Published on: July 21, 2018
Clinical potential of SKP2 as diagnostic marker and therapeutic target in small cell lung cancer
Naohisa Matsumoto1, Ken Tajima1, Fumiyuki Takahashi1
1Department 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.
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.
Insights
Researchers identified SKP2 and CKS1B as key genes in aggressive small cell lung cancer (SCLC). Targeting SKP2 offers a potential new therapy for SCLC patients, regardless of RB1 mutation status.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic advancements.
- Survival rates for SCLC have stagnated due to a lack of major treatment breakthroughs in over 15 years.
Purpose of the Study:
- To identify critical genetic vulnerabilities in SCLC.
- To discover novel therapeutic targets for SCLC treatment.
Main Methods:
- Genome-wide loss-of-function screening was employed to identify essential genes in SCLC.
- Immunohistochemistry was used to assess SKP2 expression in patient samples.
- Functional studies (knockdown) were performed to evaluate the impact of gene inhibition on SCLC cells with different RB1 statuses.
Main Results:
- SKP2 (S-phase kinase-associated protein 2) and CKS1B were identified as the most essential genes in SCLC.
- SKP2 and CKS1B are components of the SCFSKP2 complex, crucial for cell cycle regulation.
- High SKP2 expression was observed in over 95% of SCLC samples, exceeding common neuroendocrine markers.
- SKP2 inhibition demonstrated sensitivity in SCLC cell lines.
- Knockdown of SKP2 or CKS1B induced apoptosis in RB1-mutant SCLC and senescence in RB1 wild-type SCLC.
Conclusions:
- SKP2 is a promising therapeutic target for SCLC, effective irrespective of RB1 mutation status.
- The differential response (apoptosis vs. senescence) highlights distinct mechanisms of growth inhibition based on RB1 status.
- SKP2 represents a potential novel clinical diagnostic marker and therapeutic target for SCLC.
