| Literature DB >> 28059768 |
Ping Mu1, Zeda Zhang1,2, Matteo Benelli3, Wouter R Karthaus1, Elizabeth Hoover1, Chi-Chao Chen4,5, John Wongvipat1, Sheng-Yu Ku6, Dong Gao1, Zhen Cao1,5, Neel Shah1,2, Elizabeth J Adams1, Wassim Abida1, Philip A Watson1, Davide Prandi3, Chun-Hao Huang4,5, Elisa de Stanchina7, Scott W Lowe4,5,8, Leigh Ellis6, Himisha Beltran9,10, Mark A Rubin9,10, David W Goodrich6, Francesca Demichelis3,9, Charles L Sawyers11,8.
Abstract
Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. We use in vitro and in vivo human prostate cancer models to show that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR)-dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2, and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.Entities:
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Year: 2017 PMID： 28059768 PMCID： PMC5247742 DOI： 10.1126/science.aah4307
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728