VOPP1, a Determinant of the Sensitivity of Non-Small Cell Lung Cancer Cells to NAE Inhibitors

Ru-Jun Xu; Xu-Bin Bao; Ze-Hong Miao; Jin-Xue He

doi:10.1016/j.ejphar.2025.177942

VOPP1, a Determinant of the Sensitivity of Non-Small Cell Lung Cancer Cells to NAE Inhibitors

Eur J Pharmacol. 2025 Jul 10:177942. doi: 10.1016/j.ejphar.2025.177942. Online ahead of print.

Authors

Ru-Jun Xu¹, Xu-Bin Bao¹, Ze-Hong Miao¹, Jin-Xue He²

Affiliations

¹ State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
² State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China. Electronic address: jinxue_he@simm.ac.cn.

PMID: 40651787
DOI: 10.1016/j.ejphar.2025.177942

Abstract

The failure of phase III clinical trials on the NEDD8-activating enzyme (NAE) inhibitor, MLN4924, has increased the demand for sensitive biomarkers for efficient patient selection. To date, no validated sensitivity biomarkers for NAE inhibitors have been reported. The Cancer Genome Atlas data revealed that the vesicular overexpressed in cancer pro-survival protein 1 (VOPP1) was overexpressed in solid tumors, and its expression levels significantly affected the prognosis of patients with non-small cell lung cancer (NSCLC). Changes in VOPP1 levels via knockout, small interfering RNA interference, re-expression, and overexpression were positively correlated with NAE inhibitor sensitivity in both NSCLC cell lines and xenograft models. NAE inhibitors also impacted cell cycle arrest and apoptosis. Mechanistically, reduced VOPP1 expression transcriptionally downregulated the E2F transcription factor 1 (E2F1) levels, which further impeded the transcription of the chromatin licensing and DNA replication factor 1 (CDT1). Our data suggest that the VOPP1-E2F1-CDT1 axis regulates the NAE inhibitor sensitivity of NSCLC cells. Furthermore, our findings provide important insights for further evaluation of VOPP1 as a potential NAE inhibitor sensitivity biomarker in clinical settings.

Keywords: CDT1; E2F1; NAE inhibitor; VOPP1; sensitivity biomarker.