Harnessing Transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer.
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.
Dhital, Brittiny; Santasusagna, Sandra; Kirthika, Perumalraja; Xu, Michael; Li, Peiyao; Carceles-Cordon, Marc; Soni, Rajesh K.; Li, Zhuoning; Hendrickson, Ronald C.; Schiewer, Matthew J.; Kelly, William K.; Sternberg, Cora N.; Luo, Jun; Lujambio, Amaia; Cordon-Cardo, Carlos; Alvarez-Fernandez, Monica; Malumbres, Marcos; Huang, Haojie; Ertel, Adam; Domingo-Domenech, Josep; and Rodriguez-Bravo, Veronica, "Harnessing Transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer." (2023). Kimmel Cancer Center Papers, Presentations, and Grand Rounds. Paper 66.
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This article is the author's final published version in Cell Reports Medicine, Volume 4, Issue 2, February 2023, Article number 100937.
The published version is available at https://doi.org/10.1016/j.xcrm.2023.100937. Copyright © 2023 The Author(s).