顺铂
膀胱癌
癌症研究
体内
可药性
细胞内
化疗
癌细胞
医学
药理学
癌症
化学
生物
内科学
生物化学
基因
遗传学
作者
Robert T. Jones,Andrew Goodspeed,Maryam Akbarzadeh,Mathijs P. Scholtes,Hedvig Vékony,Annie Jean,Charlene B. Tilton,Saswat Mohapatra,Michael V. Orman,Stephanie P. Araki,Molishree Joshi,Teemu D. Laajala,Mahmood Javaid,Eric T. Clambey,Ryan M. Layer,Sarah J. Parker,Tokameh Mahmoudi,Tahlita C.M. Zuiverloon,Dan Theodorescu,James C. Costello
标识
DOI:10.1101/2021.03.04.433676
摘要
ABSTRACT There is an unmet need to improve efficacy of platinum-based cancer chemotherapy. Using multi-omic assessment of cisplatin-responsive and -resistant human bladder cancer cell lines and whole-genome CRISPR screens, we identified Puromycin-Sensitive Aminopeptidase, NPEPPS, as a novel driver of cisplatin resistance. NPEPPS depletion sensitizes resistant bladder cancer cells to cisplatin in vitro and in vivo . Conversely, overexpression of NPEPPS in sensitive cells increased cisplatin resistance. We show that NPEPPS affects treatment response by regulating intracellular cisplatin concentrations. Patient-derived organoids (PDOs) generated from bladder cancer samples before and after cisplatin-based treatment, and from patients who did not receive cisplatin, were evaluated for sensitivity to cisplatin and they were found to be concordant with clinical response. In PDOs, shRNA depletion or pharmacologic inhibition of NPEPPS led to increased cisplatin sensitivity, while NPEPPS overexpression had the opposite effect. Our data present NPEPPS as a novel and druggable driver of cisplatin resistance by regulating intracellular cisplatin concentrations, along with providing the preclinical data to support clinical trials combining NPEPPS inhibition with cisplatin.
科研通智能强力驱动
Strongly Powered by AbleSci AI