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

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-DomenechVeronica Rodriguez-Bravo

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number100937
JournalCell Reports Medicine
Issue number2
StatePublished - Feb 21 2023


  • AR-V7
  • chromosomal instability (CIN)
  • E2F7
  • lethal prostate cancer
  • therapy resistance

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


Dive into the research topics of 'Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer'. Together they form a unique fingerprint.

Cite this