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

Area of Science:

• Oncology
• Cancer Biology
• Genetics

Background:

• Metastatic prostate cancer (PCa) often becomes resistant to standard treatments.
• Therapy resistance in lethal PCa is linked to chromosomal instability (CIN).

Purpose of the Study:

• To identify mechanisms of CIN tolerance in therapy-refractory metastatic PCa.
• To uncover therapeutic vulnerabilities in treatment-resistant PCa.

Main Methods:

• Genomic and transcriptomic analysis of patient datasets.
• Functional genomics screening and quantitative phosphoproteomics.
• Investigated MASTL kinase activity and its role in PCa cell survival.

Main Results:

• Therapy-resistant PCa exhibits high CIN and elevated mitotic kinase levels.
• MASTL kinase identified as a specific survival vulnerability in chemotherapy-resistant PCa cells.
• MASTL upregulation is driven by androgen receptor splice variant 7 and E2F7, restraining CIN and preventing cell death.

Conclusions:

• MASTL kinase is a key component of a CIN tolerance mechanism in lethal, therapy-resistant PCa.
• Pharmacological inhibition of MASTL re-sensitizes tumors to therapy and improves survival in preclinical models.
• MASTL represents a novel therapeutic target for overcoming treatment resistance in metastatic prostate cancer.