SOX2 promotes lineage plasticity and antiandrogen resistance in TP53-and RB1-deficient prostate cancer

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 BeltranMark A. Rubin, David W. Goodrich, Francesca Demichelis, Charles L. Sawyers

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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.

Original languageEnglish (US)
Article numberaah4307
JournalScience
Volume355
Issue number6320
DOIs
Publication statusPublished - Jan 6 2017
Externally publishedYes

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Mu, P., Zhang, Z., Benelli, M., Karthaus, W. R., Hoover, E., Chen, C. C., ... Sawyers, C. L. (2017). SOX2 promotes lineage plasticity and antiandrogen resistance in TP53-and RB1-deficient prostate cancer. Science, 355(6320), [aah4307]. https://doi.org/10.1126/science.aah4307