Targeted Inhibition of SCFSKP2 Confers Anti-Tumor Activities Resulting in a Survival Benefit in Osteosarcoma

Authors

Jichuan Wang
Alexander Ferrena
Ranxin Zhang
Swapnil Singh
Valentina Viscarret
Waleed Al-Harden
Osama Aldahamsheh
Hasibagan Borjihan
Amit Singla
Simon Yaguare
Janet Tingling
Xiaolin Zi
Yungtai Lo
Richard Gorlick
Edward L Schwartz
Hongling Zhao
Rui Yang
David S Geller
Deyou Zheng
Bang H Hoang

Publication Date

3-1-2024

Journal

Oncogene

DOI

10.1038/s41388-024-02942-4

PMID

38355807

PMCID

PMC10959747

PubMedCentral® Posted Date

2-14-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Osteosarcoma(OS) is a highly aggressive bone cancer for which treatment has remained essentially unchanged for decades. Although OS is characterized by extensive genomic heterogeneity and instability, RB1 and TP53 have been shown to be the most commonly inactivated tumor suppressors in OS. We previously generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which largely recapitulates human OS with nearly complete penetrance. SKP2 is a repression target of pRb and serves as a substrate recruiting subunit of the SCFSKP2 complex. In addition, SKP2 plays a central role in regulating the cell cycle by ubiquitinating and promoting the degradation of p27. We previously reported the DKOAA transgenic model, which harbored a knock-in mutation in p27 that impaired its binding to SKP2. Here, we generated a novel p53-Rb1-SKP2 triple-knockout model (TKO) to examine SKP2 function and its potential as a therapeutic target in OS. First, we observed that OS tumorigenesis was significantly delayed in TKO mice and their overall survival was markedly improved. In addition, the loss of SKP2 also promoted an apoptotic microenvironment and reduced the stemness of DKO tumors. Furthermore, we found that small-molecule inhibitors of SKP2 exhibited anti-tumor activities in vivo and in OS organoids as well as synergistic effects when combined with a standard chemotherapeutic agent. Taken together, our results suggest that SKP2 inhibitors may reduce the stemness plasticity of OS and should be leveraged as next-generation adjuvants in this cancer.

Keywords

Animals, Humans, Mice, Bone Neoplasms, Carcinogenesis, Cyclin-Dependent Kinase Inhibitor p27, Mice, Knockout, Osteosarcoma, S-Phase Kinase-Associated Proteins, Tumor Microenvironment, Bone cancer

Published Open-Access

yes

Recommended Citation

Wang, Jichuan; Ferrena, Alexander; Zhang, Ranxin; et al., "Targeted Inhibition of SCFSKP2 Confers Anti-Tumor Activities Resulting in a Survival Benefit in Osteosarcoma" (2024). Faculty, Staff and Student Publications. 5208.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5208