Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer.
Publication/Presentation Date
2-21-2023
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.
Volume
4
Issue
2
First Page
100937
Last Page
100937
ISSN
2666-3791
Published In/Presented At
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. (2023). Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer. Cell reports. Medicine, 4(2), 100937. https://doi.org/10.1016/j.xcrm.2023.100937
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
36787737
Department(s)
Administration and Leadership
Document Type
Article