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.

• Authors: Brittiny Dhital, Sandra Santasusagna, Perumalraja Kirthika, Michael Xu, Peiyao Li, Marc Carceles-Cordon, Rajesh K Soni, Zhuoning Li, Ronald C Hendrickson, Matthew J Schiewer, William K Kelly, Cora N Sternberg, Jun Luo, Amaia Lujambio, Carlos Cordon-Cardo, Monica Alvarez-Fernandez, Marcos Malumbres, Haojie Huang, Adam Ertel, Josep Domingo-Domenech, Veronica Rodriguez-Bravo
• Journal: Cell reports. Medicine (Cell Rep Med) Vol. 4 Issue 2 Pg. 100937 (02 21 2023) ISSN: 2666-3791 [Electronic] United States
• PMID: 36787737 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Receptors, Androgen
• MASTL protein, human
• Microtubule-Associated Proteins
• Protein Serine-Threonine Kinases

Topics

• Male
• Humans
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism, pathology)
• Receptors, Androgen (genetics, metabolism)
• Chromosomal Instability
• Microtubule-Associated Proteins (genetics, therapeutic use)
• Protein Serine-Threonine Kinases (genetics)