Abstract
BackgroundDNA 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 bodyIn 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 non-BRCA 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.ConclusionsPARP 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.
Highlights
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
poly(ADP-ribose) polymerases (PARPs) 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
# 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
Summary
Emerging data suggest that 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 PARP inhibitors that can kill cancer cells with these defects, is a potent example of targeting therapy to molecularly defined tumor subtypes. The systematic evaluation of PAR levels, γH2AX, FANC and RAD51 foci with genomic instability features in tumor biopsies before, during and after treatment might help to identify patient populations who can be classified as responders or non-responders to PARP inhibitors. The heterogeneity of the tumor could always limit the evaluation of specific biomarkers, especially when the analysis is performed on a small amount of tissue (tissue microarrays, TMA) by IHC or FFPE
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