Targeting poly(ADP-ribose) polymerase and the c-Myb-regulated DNA damage response pathway in castration-resistant...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Androgen deprivation therapy (ADT) is standard for advanced prostate cancer (PCa).
• Most patients develop resistance to ADT, leading to tumor recurrence.
• The role of MYB in ADT resistance and PCa progression is under investigation.

Purpose of the Study:

• To investigate the role of MYB in prostate cancer progression following androgen deprivation.
• To identify shared target genes between MYB and the androgen receptor (AR).
• To explore novel therapeutic strategies targeting MYB and DNA damage response (DDR) pathways in PCa.

Main Methods:

• Investigated MYB transcriptional activation by ADT or AR silencing in PCa cells and mouse xenografts.
• Utilized microarray analysis to identify shared target genes between MYB and AR, focusing on DDR proteins.
• Evaluated the efficacy of combination therapies involving MYB knockdown, DDR gene inhibition (BRCA1, TOPBP1), and checkpoint kinase inhibitors (AZD7762) with PARP inhibitors (olaparib).

Main Results:

• MYB is transcriptionally activated by ADT or AR silencing and promotes PCa growth.
• MYB and AR share common target genes involved in DNA damage response (DDR).
• MYB may compensate for AR loss in regulating DDR pathways in resistant PCa.
• Gene signatures involving AR, MYB, and DDR genes correlate with aggressive PCa phenotypes and poor survival.
• Combination therapies targeting MYB, BRCA1, TOPBP1, or Chk1 with olaparib enhance PCa cell cytotoxicity.

Conclusions:

• MYB plays a critical role in prostate cancer progression and resistance to androgen deprivation.
• MYB can supplant AR in regulating DDR pathways, contributing to treatment resistance.
• Targeting MYB and key DDR pathway components (e.g., PARP, ATR, Chk1) presents a promising therapeutic avenue for advanced and castration-resistant prostate cancer.