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

Mu, Ping; Zhang, Zeda; Benelli, Matteo; Karthaus, Wouter R; Hoover, Elizabeth; Chen, Chi-Chao; Wongvipat, John; Ku, Sheng-Yu; Gao, Dong; Cao, Zhen; Shah, Neel; Adams, Elizabeth J; Abida, Wassim; Watson, Philip A; Prandi, Davide; Huang, Chun-Hao; de Stanchina, Elisa; Lowe, Scott W; Ellis, Leigh; Beltran, Himisha; ... (2017). SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science, 355(6320), pp. 84-88. American Association for the Advancement of Science 10.1126/science.aah4307

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie

UniBE Contributor:

Rubin, Mark Andrew

Subjects:

500 Science
500 Science > 570 Life sciences; biology

ISSN:

0036-8075

Publisher:

American Association for the Advancement of Science

Language:

English

Submitter:

Marla Rittiner

Date Deposited:

08 Mar 2018 14:41

Last Modified:

08 Mar 2018 14:44

Publisher DOI:

10.1126/science.aah4307

PubMed ID:

28059768

BORIS DOI:

10.7892/boris.110876

URI:

https://boris.unibe.ch/id/eprint/110876

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