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

TitleSOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer.
Publication TypeJournal Article
Year of Publication2017
AuthorsMu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen C-C, Wongvipat J, Ku S-Y, Gao D, Cao Z, Shah N, Adams EJ, Abida W, Watson PA, Prandi D, Huang C-H, de Stanchina E, Lowe SW, Ellis L, Beltran H, Rubin MA, Goodrich DW, Demichelis F, Sawyers CL
JournalScience
Volume355
Issue6320
Pagination84-88
Date Published2017 Jan 06
ISSN1095-9203
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.

DOI10.1126/science.aah4307
Alternate JournalScience
PubMed ID28059768
PubMed Central IDPMC5247742
Grant ListU54 OD020355 / OD / NIH HHS / United States
P50 CA092629 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA155169 / CA / NCI NIH HHS / United States
R01 CA116337 / CA / NCI NIH HHS / United States
R21 CA179907 / CA / NCI NIH HHS / United States
P01 CA013106 / CA / NCI NIH HHS / United States
T32 CA009072 / CA / NCI NIH HHS / United States