Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer.
AR-V7
E2F7
MASTL
chromosomal instability (CIN)
lethal prostate cancer
therapy resistance
Journal
Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894
Informations de publication
Date de publication:
21 02 2023
21 02 2023
Historique:
received:
12
08
2022
revised:
27
09
2022
accepted:
18
01
2023
pubmed:
15
2
2023
medline:
25
2
2023
entrez:
14
2
2023
Statut:
ppublish
Résumé
Metastatic prostate cancer (PCa) inevitably acquires resistance to standard therapy preceding lethality. Here, we unveil a chromosomal instability (CIN) tolerance mechanism as a therapeutic vulnerability of therapy-refractory lethal PCa. Through genomic and transcriptomic analysis of patient datasets, we find that castration and chemotherapy-resistant tumors display the highest CIN and mitotic kinase levels. Functional genomics screening coupled with quantitative phosphoproteomics identify MASTL kinase as a survival vulnerability specific of chemotherapy-resistant PCa cells. Mechanistically, MASTL upregulation is driven by transcriptional rewiring mechanisms involving the non-canonical transcription factors androgen receptor splice variant 7 and E2F7 in a circuitry that restrains deleterious CIN and prevents cell death selectively in metastatic therapy-resistant PCa cells. Notably, MASTL pharmacological inhibition re-sensitizes tumors to standard therapy and improves survival of pre-clinical models. These results uncover a targetable mechanism promoting high CIN adaptation and survival of lethal PCa.
Identifiants
pubmed: 36787737
pii: S2666-3791(23)00029-0
doi: 10.1016/j.xcrm.2023.100937
pmc: PMC9975292
pii:
doi:
Substances chimiques
Receptors, Androgen
0
MASTL protein, human
EC 2.7.11.1
Microtubule-Associated Proteins
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
100937Subventions
Organisme : NCI NIH HHS
ID : R01 CA237398
Pays : United States
Organisme : NCI NIH HHS
ID : K22 CA207458
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA207311
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA261925
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA087497
Pays : United States
Organisme : NIH HHS
ID : S10 OD010598
Pays : United States
Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing financial interests.
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