Article

Targeting RSK2 enhances the efficacy of IGF1R inhibitor against triple-negative breast cancer via antagonizing IGF1/IGF1R signaling mediated by GATA3-IGFBP5 pathway

Tian-jiao Shan1,2, Lan-ya Li1,2, Xiao-ya Wan1,2, Yi-zhi Li1,2, Ting Jiang1,2, Zong-lin Chen3, Xiao-hui Yu4, Yan Cheng1,2,3,5
1 Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China
2 Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha 410011, China
3 Clinical Research Center for Breast Disease in Hunan Province, Changsha 410011, China
4 Department of Pathology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Cancer Hospital, Central South University, Changsha 410008, China
5 NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha 410013, China
Correspondence to: Yan Cheng: yancheng@csu.edu.cn,
DOI: 10.1038/s41401-025-01673-w
Received: 2 June 2025
Accepted: 11 September 2025
Advance online: 7 January 2026

Abstract

Targeting the IGF1 system holds promise as a therapeutic approach for breast cancer. However, the intricate nature of IGF1 signaling and suboptimal drug combinations have resulted in limited clinical success. This study demonstrates that silencing p90 ribosomal S6 kinase 2 (RSK2), a downstream effector of the Ras/ERK pathway, inhibits IGF1 signaling by upregulating the expression and secretion of IGFBP5, a potent inhibitor of the IGF1-IGF1R axis that competes with IGF1 for binding. Mechanistically, GATA3 is identified as a novel transcription factor for IGFBP5, and RSK2 promotes GATA3 degradation by directly binding and phosphorylating it at serine 308, thus suppressing IGFBP5 transcription. Moreover, combined treatment with the RSK2 inhibitor LJH685 and the IGF1R inhibitor PPP significantly reduces metastasis of triple-negative breast cancer (TNBC) in both in vitro and in vivo models. These findings uncover new targets for synergistic antitumor therapy in TNBC and suggest that concurrent inhibition of IGF1R and RSK2 may offer an effective combinatorial treatment strategy.
Keywords: TNBC; IGF1; IGFBP5; RSK2; GATA3

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