Acquisition of taxane resistance by p53 inactivation in ovarian cancer cells  

作　　者：Changfa Shu Xi Zheng Alafate Wuhafu Danielle Cicka Sean Doyle Qiankun Niu Dacheng Fan Kun Qian Andrey AIvanov Yuhong Du Xiulei Mo Haian Fu 

机构地区：[1]Department of Pharmacology and Chemical Biology,Emory University School of Medicine,Atlanta,GA 30322,USA [2]Department of Gynecology and Obstetrics,The Third Xiangya Hospital of Central South University,Changsha 410013,China [3]Cancer Institute,the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310052,China [4]The First Affiliated Hospital,Medical School of Xi’an Jiaotong University,Xi’an 710061,China [5]Emory Chemical Biology Discovery Center,Emory University School of Medicine,Atlanta,GA 30322,USA [6]Department of Hematology and Medical Oncology and Winship Cancer Institute,Emory University,Atlanta,GA 30322,USA

出　　处：《Acta Pharmacologica Sinica》2022年第9期2419-2428,共10页中国药理学报（英文版）

基　　金：This work was supported by the Georgia Research Alliance(Distinguished Investigator award to HF);the NCI Emory Lung Cancer SPORE Career Enhancement Program(P50CA217691 to XM);the Imagine,Innovate and Impact(I3)Funds from the Emory School of Medicine;and through the Georgia CTSA NIH award(UL1-TR002378)and Winship Cancer Institute(NIH 5P30CA138292).

摘　　要：Ovarian cancer is one of the most common gynecologic malignancies in women and has a poor prognosis.Taxanes are a class of standard first-line chemotherapeutic agents for the treatment of ovarian cancer.However,tumor-intrinsic and acquired resistance to taxanes poses major challenges to improving clinical outcomes.Hence,there is an urgent clinical need to understand the mechanisms of resistance in order to discover potential biomarkers and therapeutic strategies to increase taxane sensitivity in ovarian cancer.Here,we report the identification of an association between the TP53 status and taxane sensitivity in ovarian cancer cells through complementary experimental and informatics approaches.We found that TP53 inactivation is associated with taxane resistance in ovarian cancer cells,supported by the evidence from(i)drug sensitivity profiling with bioinformatic analysis of large-scale cancer therapeutic response and genomic datasets and(ii)gene signature identification based on experimental isogenic cell line models.Further,our studies revealed TP53-dependent gene expression patterns,such as overexpression of ACSM3,as potential predictive biomarkers of taxane resistance in ovarian cancer.The TP53-dependent hyperactivation of the WNT/β-catenin pathway discovered herein revealed a potential vulnerability to exploit in developing combination therapeutic strategies.Identification of this genotype-phenotype relationship between the TP53 status and taxane sensitivity sheds light on TP53-directed patient stratification and therapeutic discoveries for ovarian cancer treatment.

关 键 词：PACLITAXEL DOCETAXEL Ovarian cancer TP53 ACSM3 WNT signaling 

分 类 号：R734.2[医药卫生—肿瘤]