Blocking p85β nuclear translocation by importazole enhances Alpelisib efficacy against PIK3CA-helical-domain-mutant tumors

Baoyu He; Xiangyu Li; Meilian Yao; Yanhua Zhang; Xinyuan Zhou; Jun Gu; Yujun Hao; Dong Zhang; Longci Sun

doi:10.1016/j.bbrc.2025.151324

Blocking p85β nuclear translocation by importazole enhances Alpelisib efficacy against PIK3CA-helical-domain-mutant tumors

Biochem Biophys Res Commun. 2025 Jan 13:748:151324. doi: 10.1016/j.bbrc.2025.151324. Online ahead of print.

Authors

Baoyu He¹, Xiangyu Li², Meilian Yao², Yanhua Zhang², Xinyuan Zhou³, Jun Gu², Yujun Hao⁴, Dong Zhang⁵, Longci Sun⁶

Affiliations

¹ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China; Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, 272029, China.
² State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China.
³ Department of Spleen and Stomach, Shanxi Traditional Chinese Medical Hospital, Taiyuan, Shanxi, 030001, China.
⁴ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China. Electronic address: [email protected].
⁵ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China. Electronic address: [email protected].
⁶ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China; Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. Electronic address: [email protected].

PMID: 39823894
DOI: 10.1016/j.bbrc.2025.151324

Abstract

PIK3CA, which encodes protein p110α, is one of the most frequently mutated oncogenes and a promising drug-target for human cancer. Previously, we demonstrate that p85β is released from PI3K complex which contain PIK3CA helical domain mutations and translocates into nucleus to regulate tri-methylation of H3K27, thereby promoting tumorigenicity. Here, we identify DIRAS2 and SOWAHB as target genes of nuclear p85β in PIK3CA-helical-domain-mutant tumors. DIRAS2 and SOWAHB are tumor suppressive genes, whose expression are repressed by nuclear p85β through histone methyltransferase EZH2. More importantly, combination of PI3K inhibitor and importin-β inhibitor effectively inhibits the growth of PIK3CA-helical-domain-mutant tumors by synchronously blocking both AKT signaling and nuclear p85β/DIRAS2 and SOWAHB axis. In this study, we evaluate the combination effect of Alpelisib and Importazole for PIK3CA helical domain mutant tumors and demonstrate its underlying mechanism.

Keywords: Alpelisib; Importazole; PIK3CA-Helical-domain-mutant tumors; p85β.