FSIP1 enhances the therapeutic sensitivity to CDK4/6 inhibitors in triple-negative breast cancer patients by activating the Nanog pathway

• DOI: 10.1007/s11427-023-2343-y
• Publication Date: 2023-07-18T00:01:53Z
• Authors: Guanglei Chen; Lisha Sun; Xi Gu; Liping Ai; Jie Yang; Zhan Zhang; Pengjie Hou; Yining Wang; Xunyan Ou; Xiaofan Jiang; Xinbo Qiao; Qingtian Ma; Nan Niu; Jinqi Xue; Hao Zhang; Yongliang Yang; Caigang Liu
• Keywords: Lung Neoplasms; Cell Line, Tumor; Seminal Plasma Proteins; Humans; Cyclin-Dependent Kinase 4; Triple Negative Breast Neoplasms; Cell Cycle Checkpoints; Carrier Proteins; 3. Good health; Cell Proliferation

CDK4/6 inhibitors are routinely recommended agents for the treatment of advanced HR+HER2- breast cancer. However, their therapeutic effectiveness in triple-negative breast cancer (TNBC) remains controversial. Here, we observed that the expression level of fibrous sheath interacting protein 1 (FSIP1) could predict the treatment response of TNBC to CDK4/6 inhibitors. High FSIP1 expression level was related to a poor prognosis in TNBC, which was associated with the ability of FSIP1 to promote tumor cell proliferation. FSIP1 downregulation led to slowed tumor growth and reduced lung metastasis in TNBC. FSIP1 knockout caused cell cycle arrest at the G0/G1 phase and reduced treatment sensitivity to CDK4/6 inhibitors by inactivating the Nanog/CCND1/CDK4/6 pathway. FSIP1 could form a complex with Nanog, protecting it from ubiquitination and degradation, which may facilitate the rapid cell cycle transition from G0/G1 to S phase and exhibit enhanced sensitivity to CDK4/6 inhibitors. Our findings suggest that TNBC patients with high FSIP1 expression levels may be suitable candidates for CDK4/6 inhibitor treatment.