Format

Send to

Choose Destination
Science. 2017 Jan 6;355(6320):84-88. doi: 10.1126/science.aah4307.

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

Author information

1
Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
2
Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Centre for Integrative Biology, University of Trento, Trento, Italy.
4
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
5
Weill Cornell Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
6
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, New York, NY 14263, USA.
7
Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
8
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
9
Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA.
10
Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY 10021, USA.
11
Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. sawyersc@mskcc.org.

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.

Comment in

PMID:
28059768
PMCID:
PMC5247742
DOI:
10.1126/science.aah4307
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center