Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer Journal Article

   

Authors:	Dhital, B.; Santasusagna, S.; Kirthika, P.; Xu, M.; Li, P.; Carceles-Cordon, M.; Soni, R. K.; Li, Z.; Hendrickson, R. C.; Schiewer, M. J.; Kelly, W. K.; Sternberg, C. N.; Luo, J.; Lujambio, A.; Cordon-Cardo, C.; Alvarez-Fernandez, M.; Malumbres, M.; Huang, H.; Ertel, A.; Domingo-Domenech, J.; Rodriguez-Bravo, V.
Article Title:	Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer
Abstract:	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. © 2023 The Author(s)
Keywords:	therapy resistance; e2f7; ar-v7; mastl; chromosomal instability (cin); lethal prostate cancer
Journal Title:	Cell Reports Medicine
Volume:	4
Issue:	2
ISSN:	2666-3791
Publisher:	Cell Press
Date Published:	2023-02-21
Start Page:	100937
Language:	English
DOI:	10.1016/j.xcrm.2023.100937
PUBMED:	36787737
PROVIDER:	scopus
PMCID:	PMC9975292
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85148335176&doi=10.1016%2fj.xcrm.2023.100937&partnerID=40&md5=f3f34555098cdaf2c493dea0467bf04f
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- Export Date: 1 March 2023 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/203228