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Review
. 2016 Nov 24;35(1):179.
doi: 10.1186/s13046-016-0456-2.

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

Aniello Cerrato  1 , Francesco Morra  2 , Angela Celetti  3
Affiliations
Review

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

Aniello Cerrato et al. J Exp Clin Cancer Res. .

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 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.

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: Assays; BRCA1/2 and BRCAness; Cancer; Clinical trials; DNA damage response; HR proficiency and PARP activity; PARP enzymes; PARP inhibitors.

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Figures

Fig. 1
Fig. 1
Diagram of targeted DDR pathways. In the lower part of the figure the DDR mechanisms and the related proteins involved are represented. In the upper part of the figure the targeting strategy for the corresponding defective DDR mechanisms are shown
Fig. 2
Fig. 2
Synthetic Lethality of PARP-inhibitors in BRCA Tumors. Poly(ADP-ribose) polymerases (PARPs) repair DNA SSBs through the BER pathway. PARP inhibitors, such as olaparib, prevent repair of the SSBs, resulting in the generation of DNA DSBs. Cancer cells with a deficient homologous recombination (BRCA1/BRCA2 mutations) required for the repair of the DSBs do not compensate for the increased DNA damage caused by the inhibition of PARP enzymes and appear to be especially sensitive to treatment with these drugs
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