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.
Science (New York, N.Y.). 2017 Jan 06 [Epub]
Ping Mu, Zeda Zhang, Matteo Benelli, Wouter R Karthaus, Elizabeth Hoover, Chi-Chao Chen, John Wongvipat, Sheng-Yu Ku, Dong Gao, Zhen Cao, Neel Shah, Elizabeth J Adams, Wassim Abida, Philip A Watson, Davide Prandi, Chun-Hao Huang, Elisa de Stanchina, Scott W Lowe, Leigh Ellis, Himisha Beltran, Mark A Rubin, David W Goodrich, Francesca Demichelis, Charles L Sawyers
Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA., Centre for Integrative Biology, University of Trento, Trento, Italy., Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA., Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, New York, NY 14263, USA., Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA., Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA., Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. .