Identification of Novel Biomarkers of Homologous Recombination Defect in DNA Repair to Predict Sensitivity of Prostate Cancer Cells to PARP-Inhibitors.

Daniela Criscuolo,Riccardo Giannella,Angela Celetti,Francesco Morra,Aniello Cerrato

doi:10.3390/ijms20123100

Abstract

One of the most common malignancies in men is prostate cancer, for which androgen deprivation is the standard therapy. However, prostate cancer cells become insensitive to anti-androgen treatment and proceed to a castration-resistant state with limited therapeutic options. Therefore, besides the androgen deprivation approach, novel biomarkers are urgently required for specific targeting in this deadly disease. Recently, germline or somatic mutations in the homologous recombination (HR) DNA repair genes have been identified in at least 20–25% of metastatic castration-resistant prostate cancers (mCRPC). Defects in genes involved in HR DNA repair can sensitize cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors, a class of drugs already approved by the Food and Drug Administration (FDA) for breast and ovarian cancer carrying germline mutations in BRCA1/2 genes. For advanced prostate cancer carrying Breast cancer1/2 (BRCA1/2) or ataxia telengiectasia mutated (ATM) mutations, preclinical studies and clinical trials support the use of PARP-inhibitors, which received breakthrough therapy designation by the FDA. Based on these assumptions, several trials including DNA damage response and repair (DDR) targeting have been launched and are ongoing for prostate cancer. Here, we review the state-of-the-art potential biomarkers that could be predictive of cancer cell synthetic lethality with PARP inhibitors. The identification of key molecules that are affected in prostate cancer could be assayed in future clinical studies to better stratify prostate cancer patients who might benefit from target therapy.

Highlights

The human genome is constantly exposed to endogenous and exogenous genotoxic stress
To preserve the genome integrity, eukaryotic cells have evolved a complex array of DNA repair pathways [1] including base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR) pathways that repair the damage limited to a single DNA strand as single strand breaks (SSBs) or base modification
In the castration-resistant prostate cancer (CRPC) setting, the response rate to conventional chemotherapy was highly variable in different studies, possibly due to patient heterogeneity, and to the plasticity of cancer cells and the different types of somatic alterations occurring in the androgen receptor (AR) geneconsisting of AR genomic amplification, mutation, and duplication of an enhancer upstream of AR- that increases its expression

Summary

Ongoing Prostate Cancer Clinical Trials Involving PARP Inhibitors

Recent studies have evaluated several PARP inhibitors, including Rucaparib, Olaparib, Niraparib, Veliparib, and Talazoparib, for their PARP-trapping potency. The first clinical study involving PARP inhibitors in prostate cancer treatment was conducted at the Royal Marsden National Health Service (NHS) Foundation Trust (United Kingdom) and the Netherlands Cancer Institute (The Netherlands) in 2009 [47] In this phase I trial, 60 patients with castration-resistant prostate cancer, carrying BRCA1/2 mutations and refractory to standard therapies, were treated with escalating doses of Olaparib. Besides Olaparib, several PARP inhibitors, such as Rucaparib, Niraparib, and Talazoparib have been included in ongoing clinical trials for the treatment of prostate cancer. The inhibition of the AR signaling pathway with abiraterone may induce a DNA repair deficiency status (a so-called BRCAness state), a condition that could be investigated using concurrent PARP blockade with Olaparib [55,56,57,58,59,60] These preclinical data support the idea that the androgen receptor may promote DNA repair, through activating the transcription of DNA-dependent protein kinase [61]. As suggested by preclinical investigations, novel combinatorial strategies including immune checkpoint inhibitors, epigenetic and/or DDR targeting agents are envisaged as new therapeutic approaches in genito-urinary malignancies [41,69,70]

Combinations of PARP-Inhibitors with Immune-Checkpoint Inhibitors

Findings

Conclusions