Title | Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Dhital B, Santasusagna S, Kirthika P, Xu M, Li P, Carceles-Cordon M, Soni RK, Li Z, Hendrickson RC, Schiewer MJ, Kelly WK, Sternberg CN, Luo J, Lujambio A, Cordon-Cardo C, Alvarez-Fernandez M, Malumbres M, Huang H, Ertel A, Domingo-Domenech J, Rodriguez-Bravo V |
Journal | Cell Rep Med |
Volume | 4 |
Issue | 2 |
Pagination | 100937 |
Date Published | 2023 Feb 21 |
ISSN | 2666-3791 |
Keywords | Chromosomal Instability, Humans, Male, Microtubule-Associated Proteins, Prostatic Neoplasms, Castration-Resistant, Protein Serine-Threonine Kinases, Receptors, Androgen |
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. |
DOI | 10.1016/j.xcrm.2023.100937 |
Alternate Journal | Cell Rep Med |
PubMed ID | 36787737 |
PubMed Central ID | PMC9975292 |
Grant List | R01 CA207311 / CA / NCI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States R01 CA261925 / CA / NCI NIH HHS / United States R01 CA237398 / CA / NCI NIH HHS / United States K22 CA207458 / CA / NCI NIH HHS / United States |