Intact regulation of G1/S transition renders esophageal squamous cell carcinoma sensitive to PI3Kαinhibitors  

作　　者：Xu Zhang Yuxiang Wang Xi Zhang Yanyan Shen Kang Yang Qingyang Ma Yuemei Qiao Jiajie Shi Yi Wang Lan Xu Biyu Yang Gaoxiang Ge Landian Hu Xiangyin Kong Chunhao Yang Yi Chen Jian Ding Linghua Meng 

机构地区：[1]Division of Anti-tumor Pharmacology,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [2]University of Chinese Academy of Sciences,Beijing,100049,China [3]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing,210023,China [4]Key Laboratory of Tissue Microenvironment and Tumor,Shanghai Institute of Nutrition and Health,Chinese Academy of Sciences,Shanghai,200031,China [5]State Key Laboratory of Cell Biology,Shanghai Institute of Biochemistry and Cell Biology,Center for Excellence in Molecular Cell Science,Chinese Academy of Sciences,Shanghai,200031,China [6]Department of Medicinal Chemistry,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China

出　　处：《Signal Transduction and Targeted Therapy》2023年第5期2315-2328,共14页信号转导与靶向治疗（英文）

基　　金：supported by the Lingang Laboratory (LG202103-02-03);National Natural Science Foundation of China (82173832,81973345 and 82104199);the State Key Laboratory of Drug Research (SIMM2205KF-05);Science and Technology Commission of Shanghai Municipality (22ZR1474400);“Personalized Medicines-Molecular Signature-based Drug Discovery and Development”,Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020111).

摘　　要：Phosphatidylinositol 3-kinase alpha(PI3Kα)inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma(ESCC).It is of great importance to identify potential biomarkers to predict or monitor the efficacy of PI3Kαinhibitors in an aim to improve the clinical responsive rate in ESCC.Here,ESCC PDXs with CCND1 amplification were found to be more sensitive to CYH33,a novel PI3Kα-selective inhibitor currently in clinical trials for the treatment of advanced solid tumors including ESCC.Elevated level of cyclin D1,p21 and Rb was found in CYH33-sensitive ESCC cells compared to those in resistant cells.CYH33 significantly arrested sensitive cells but not resistant cells at G1 phase,which was associated with accumulation of p21 and suppression of Rb phosphorylation by CDK4/6 and CDK2.Hypo-phosphorylation of Rb attenuated the transcriptional activation of SKP2 by E2F1,which in turn hindered SKP2-mediated degradation of p21 and reinforced accumulation of p21.Moreover,CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33.These findings provided mechanistic rationale to evaluate PI3Kαinhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb.

关 键 词：ESOPHAGEAL SQUAMOUS RENDER 

分 类 号：R735.1[医药卫生—肿瘤]