title: SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer.
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.
authors.affiliation: Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Mu
authors.affiliation: Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.|Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Zeda
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Benelli
authors.affiliation: Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Wouter R
authors.initials: WR
authors.lastname: Karthaus
authors.affiliation: Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hoover
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.|Weill Cornell Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: John
authors.initials: J
authors.lastname: Wongvipat
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, New York, NY 14263, USA.
authors.forename: Sheng-Yu
authors.initials: SY
authors.lastname: Ku
authors.affiliation: Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Gao
authors.affiliation: Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.|Weill Cornell Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.|Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Neel
authors.initials: N
authors.lastname: Shah
authors.affiliation: Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Adams
authors.affiliation: Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Wassim
authors.initials: W
authors.lastname: Abida
authors.affiliation: Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Watson
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Prandi
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.|Weill Cornell Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.|Weill Cornell Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.|Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, New York, NY 14263, USA.
authors.forename: Leigh
authors.initials: L
authors.lastname: Ellis
authors.affiliation: Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA.|Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY 10021, USA.
authors.forename: Himisha
authors.initials: H
authors.lastname: Beltran
authors.affiliation: Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA.|Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY 10021, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, New York, NY 14263, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Goodrich
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento, Italy.|Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.affiliation: Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. sawyersc@mskcc.org.|Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D001549:Benzamides; D045744:Cell Line, Tumor; D019070:Cell Lineage; D000066670:Cell Plasticity; D006801:Humans; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D056286:Retinoblastoma Binding Proteins / Q000235:genetics*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D000726:Androgen Antagonists; D001549:Benzamides; D009570:Nitriles; C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D010669:Phenylthiohydantoin; C540278:enzalutamide; D044767:Ubiquitin-Protein Ligases