Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis.
Animals
Antineoplastic Agents
/ pharmacology
Benzamides
Carcinoma, Neuroendocrine
Cell Line, Tumor
Cell Plasticity
/ drug effects
Drug Resistance, Neoplasm
Humans
Male
Mice
Neoplastic Stem Cells
/ drug effects
Nitriles
Phenylthiohydantoin
Prostatic Neoplasms, Castration-Resistant
/ drug therapy
Receptors, Androgen
/ drug effects
Signal Transduction
Tumor Microenvironment
/ drug effects
BMP-SMAD signaling
CP: Cancer
TP53
androgen receptor signaling
prostate cancer
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
05 04 2022
05 04 2022
Historique:
received:
22
10
2020
revised:
18
09
2021
accepted:
09
03
2022
entrez:
6
4
2022
pubmed:
7
4
2022
medline:
9
4
2022
Statut:
ppublish
Résumé
Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: androgen receptor (AR) pathway + prostate cancer (PC) (ARPC), mesenchymal and stem-like PC (MSPC), and neuroendocrine PC (NEPC). A sizable proportion of castration-resistant and metastatic stage PC (M-CRPC) cases are admixtures of ARPC and MSPC. Analysis of clinical datasets and mechanistic studies indicates that MSPC arises from ARPC as a consequence of therapy-induced lineage plasticity. AR blockade with enzalutamide induces (1) transcriptional silencing of TP53 and hence dedifferentiation to a hybrid epithelial and mesenchymal and stem-like state and (2) inhibition of BMP signaling, which promotes resistance to AR inhibition. Enzalutamide-tolerant LNCaP cells re-enter the cell cycle in response to neuregulin and generate metastasis in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibits efficacy in models of ARPC and MSPC or MSPC, respectively. These results define MSPC, trace its origin to therapy-induced lineage plasticity, and reveal its sensitivity to HER2/3 inhibition.
Identifiants
pubmed: 35385726
pii: S2211-1247(22)00343-6
doi: 10.1016/j.celrep.2022.110595
pmc: PMC9414743
mid: NIHMS1797327
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Benzamides
0
Nitriles
0
Receptors, Androgen
0
Phenylthiohydantoin
2010-15-3
enzalutamide
93T0T9GKNU
Banques de données
ClinicalTrials.gov
['NCT01946165']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
110595Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197566
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA224079
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA224044
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests F.G.G. declares no competing interests. E.E. is a formal advisor to Janssen, Sanofi Merck, Novartis, Roche, Myovant, Pfizer, Astellas, AAA, and Astra Zeneca, and she has research fundings from Astellas, Janssen, and Pfizer. C.J.L. is an advisor with honoraria to Merck, Sharp & Dohme, Bayer, and Amgen, and he receives clinical grants from Janssen, ORIC Pharmaceuticals, Novartis, and Aragon Pharmaceuticals. Y.C. has stock ownership and received royalties from Oric Pharmaceuticals.
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