Use of poly ADP-ribose polymerase [PARP] inhibitors in cancer cells bearing DDR defects: the rationale for their inclusion in the clinic

Cerrato et al. Journal of Experimental & Clinical Cancer Research (2016) 35:179 DOI 10.1186/s13046-016-0456-2 REVIEW Open Access Use of poly ADP-ribose polymerase [PARP] inhibitors in cancer cells bearing DDR defects: the rationale for their inclusion in the clinic Aniello Cerrato*, Francesco Morra and Angela Celetti* Abstract Background: DNA damage response (DDR) defects imply genomic instability and favor tumor progression but make the cells vulnerable to the pharmacological inhibition of the DNA repairing enzymes. Targeting cellular proteins like PARPs, which cooperate and complement molecular defects of the DDR process, induces a specific lethality in DDR defective cancer cells and represents an anti-cancer strategy. Normal cells can tolerate the DNA damage generated by PARP inhibition because of an efficient homologous recombination mechanism (HR); in contrast, cancer cells with a deficient HR are unable to manage the DSBs and appear especially sensitive to the PARP inhibitors (PARPi) effects. Main body: In this review we discuss the proof of concept for the use of PARPi in different cancer types and the success and failure of their inclusion in clinical trials. The PARP inhibitor Olaparib [AZD2281] has been approved by the FDA for use in pretreated ovarian cancer patients with defective BRCA1/2 genes, and by the EMEA for maintenance therapy in platinum sensitive ovarian cancer patients with defective BRCA1/2 genes. BRCA mutations are now recognised as the molecular targets for PARPi sensitivity in several tumors. However, it is noteworthy that the use of PARPi has shown its efficacy also in nonBRCA related tumors. Several trials are ongoing to test different PARPi in different cancer types. Here we review the concept of BRCAness and the functional loss of proteins involved in DDR/HR mechanisms in cancer, including additional molecules that can influence the cancer cells sensitivity to PARPi. Given the complexity of the existing crosstalk between different DNA repair pathways, it is likely that a single biomarker may not be sufficient to predict the benefit of PARP inhibitors therapies. Novel general assays able to predict the DDR/HR proficiency in cancer cells and the PARPi sensitivity represent a challenge for a personalized therapy. Conclusions: PARP inhibition is a potentially important strategy for managing a significant subset of tumors. The discovery of both germline and somatic DNA repair deficiencies in different cancer patients, together with the development of new PARP inhibitors that can kill selectively cancer cells is a potent example of targeting therapy to molecularly defined tumor subtypes. Keywords: DNA damage response, PARP enzymes, PARP inhibitors, Cancer, BRCA1/2 and BRCAness, Clinical trials, Assays, HR proficiency and PARP activity * Correspondence: ; IEOS, CNR, via S. Pansini 5, 80131 Naples, Italy © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cerrato et al. Journal of Experimental & Clinical Cancer Research (2016) 35:179 Methodology: sources and search terms Literature from a range of sources, including PubMed and MEDLINE, were searched to identify recent reports regarding “DNA damage repair and PARP inhibitors” in addition to other terms relevant to this Review, including “Breast cancer and PARP”, “synthetic lethality”, “cancer and PARP inhibitors”, and “BRCAness”. The reference lists of key articles identified were also searched for additional relevant publications. The ClinicalTrials.gov database was searched using the term “PARP inhibitors” to identify relevant clinical trials. The key points of this review are: # The poly(ADP-ribose) polymerases (PARPs) family. # Repair of single-strand and double-strand breaks in DNA damage. # Homologous recombination repair (HRR) mechanisms. # Defects in DNA Damage Response in cancer. # BRCA1 or BRCA2 mutations. # Synthetic lethal concept # Molecular defects which cause the lack of homologous recombination and produce sensitivity to inhibitors of PARP activity. # Chromosomal instability and DNA repair foci # in vitro and ex vivo assays to predict the efficacy of PARP inhibitors. # Success and failure of PARP inhibitors in Clinical Trials. Background DNA damage response (DDR) is the cellular reaction to exogenous and endogenous genotoxic injuries that may produce DNA single strand breaks (SSBs) and DNA double strand breaks (DSBs). While SSBs are repaired by mechanisms of nucleotide excision repair (NER) or base excision repair (BER), or mismatch repair (MMR), DSBs are repaired either by the mechanism of homologous Page 2 of 13 recombination (HR), which utilizes the sister chromatid as a template for a correct replacement of the DNA sequence, or by the mechanism of non-homologous end joining (NHEJ), which is more prone to errors [1, 2]. The cellular choice of using HR or NHEJ is largely dependent on the phases of the cell cycle; NHEJ is present throughout the cell cycle, whereas HR predominates in the S and G2 phases, in order to ensure the high-fidelity preservation of genetic information [3]. If the repairing process does not occur correctly, the DNA injuries result in mutations and chromosomal aberrations which alter the cellular behavior and lead to cancer. Genes that encode for enzymatic or scaffolding proteins involved in the “core” DDR activities [BER, MMR, HR and NHEJ) are: XPA-XPG, RPA, ERCC1, DNA glycosylase, APE1, DNA polymerase β/δ/ε, XRCC1, DNA ligase 1/3, DNA ligase IV, Ku70/80, RAD50/MRE11/NBS1, BRCA1, BRCA2, and RAD51 (Fig. 1) [4–9]. Additionally, as a result of a computational analysis nearly 400 proteins have been identified in the regulation of the DDR processes [10–13], namely: the damage sensing kinases ATM/ATR, that activate a phosphorylation cascade signaling in response to the DSBs [14, 15]; DNA-PK, that cooperates with ATR and ATM to phosphorylate proteins involved in the DNA damage checkpoints and is required for NHEJ [16]; the kinases CHEK1 and CHEK2, that are responsible for slowing down the cell cycle progression to allow DNA repair [17]; and the nuclear phosphatase PTEN, that controls the transcription and the nuclear localization of the recombinase RAD51 [18–20]. Furthermore, ubiquitination, sumoylation, acetylation and methylation processes provide an additional layer of complexity targeting stability and efficiency of DDR proteins machinery [10, 12]. Since almost 56% of the identified 400 proteins are in (...truncated)