Targeting Homology-Directed Recombinational Repair (HDR) of Chromosomal Breaks to Sensitize Prostate Cancer Cells to Poly (ADP-Ribose) Polymerase (PARP) Inhibition.

摘要

Our project aims to: 1. Determine whether IR-induced BRCA1 nuclear export will sensitize prostate cancer cells to PARP1 inhibition, and to determine whether these effects are dependent on CRM1 (Months 1-12). 2. To transiently reduce nuclear BRCA1 using a tetracycline (tet)-regulated expression of tr-BRCA1 and determine its effects on HDR and sensitivity to PARP1 inhibition in prostate cancer cells (Months 12-24). 3. To validate the role of induced DSB repair deficiency and sensitivity to PARP1 inhibition in vivo with prostate tumor xenograft models (Months 24-36). Our findings to date are: IR induces synthetic lethality with PARPI in LNCaP prostate cancer. The mechanism is due to IR-mediated BRCA1 nuclear export and subsequent generation of an HDR defect. These results are dependent on p53 and CRM1. For tumors without wildtype p53, we have found that expression of a truncated BRCA1 (tr- BRCA1) can achieve similar results as IR, including BRCA1 nuclear export, inhibition of HDR, and synthetic lethality with PARPi in both p53 wildtype and mutated prostate cancer cells. We are essentially on track with our proposed timeline. Lastly, we have obtained ACURO as well as IACUC approval to start validating our observations in vivo.