Enhancing the therapeutic efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors in prostate cancer

Despite developments in recent years, outcomes remain poor for men with castrate resistant prostate cancer (CRPC). Inhibitors of poly(ADP-ribose) polymerase (PARPi), which plays a key role in the DNA damage response (DDR), are effective in men with CRPC and pre-existing aberrations in genes encoding proteins involved in homologous recombination (HR) repair of double strand DNA breaks (DSBs). However, responses are limited in patients that lack such aberrations, indicating a need to improve the efficacy of PARPi in this cohort. Experiments in this thesis show that whilst HR-proficient CRPC cells are insensitive to PARPi, treatment leads to DNA damage and activation of CHK1, the downstream effector of another key DDR protein, ataxia telangiectasia and Rad-3 related (ATR). ATR inhibition (ATRi) reverses CHK1 activation and is synergistic with PARPi in vitro in HR-proficient CRPC cells. Furthermore, combined PARPi and ATRi significantly reduces growth and vascularity of PC-3 subcutaneous xenograft tumours compared with vehicle or monotherapy, as well as the prevalence of invasive carcinoma in a genetically modified mouse model (GEMM) of p53 and PTEN deficient localised prostate cancer. Likewise, combination therapy also reduces proliferation of tumour cells within a novel ex vivo model of neuroendocrine CRPC. The role of PARP1, the predominant PARP isoform, was also explored through use of transgenic mouse models. Genetic depletion of PARP1 within prostatic epithelial cells did not alter the phenotype of glands within the normal adult mouse prostate or tumours in the aforementioned GEMM of p53 and PTEN deficient localised prostate cancer. On the contrary, siRNA mediated depletion of PARP1 reduces proliferation of CRPC cells in vitro, with simultaneous PARP2 depletion having no additional benefit, suggesting selective PARP1 inhibition may reduce off target toxicity whilst maintaining efficacy. Collectively, these results demonstrate that combined PARP and ATR inhibition is effective against HR-proficient prostate cancer and support its ongoing investigation in this setting