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Review
. 2021 Jul 23;22(15):7884.
doi: 10.3390/ijms22157884.

Moving beyond PARP Inhibition: Current State and Future Perspectives in Breast Cancer

Michela Palleschi  1 , Gianluca Tedaldi  2 , Marianna Sirico  1 , Alessandra Virga  2 , Paola Ulivi  2 , Ugo De Giorgi  1
Affiliations
Review

Moving beyond PARP Inhibition: Current State and Future Perspectives in Breast Cancer

Michela Palleschi et al. Int J Mol Sci. .

Abstract

Breast cancer is the most frequent and lethal tumor in women and finding the best therapeutic strategy for each patient is an important challenge. PARP inhibitors (PARPis) are the first, clinically approved drugs designed to exploit synthetic lethality in tumors harboring BRCA1/2 mutations. Recent evidence indicates that PARPis have the potential to be used both in monotherapy and combination strategies in breast cancer treatment. In this review, we show the mechanism of action of PARPis and discuss the latest clinical applications in different breast cancer treatment settings, including the use as neoadjuvant and adjuvant approaches. Furthermore, as a class, PARPis show many similarities but also certain critical differences which can have essential clinical implications. Finally, we report the current knowledge about the resistance mechanisms to PARPis. A systematic PubMed search, using the entry terms "PARP inhibitors" and "breast cancer", was performed to identify all published clinical trials (Phase I-II-III) and ongoing trials (ClinicalTrials.gov), that have been reported and discussed in this review.

Keywords: PARP inhibitor resistance; PARP inhibitors; breast cancer.

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Conflict of interest statement

M.P. has received advisory board fees from Novartis; U.D.G. has received advisory board or consultant fees from Merck Sharp & Dohme, Bristol Myers Squibb, Janssen, Astellas, Sanofi, Bayer, Pfizer, Ipsen, Novartis, and Pharmamar and institutional research grants from Astrazeneca, Sanofi, and Roche.

Figures

Figure 1
Figure 1
When a DSB occurs in the DNA (A), the MRN complex recognizes the damage (B) and starts 5′ strand degradation to get a 3′ ssDNA free to be coated by RPA and ATM is activated by phosphorylation (C). The interaction of RPA and RAD51 repairs the damage with the support of BRCA1-BARD1 and BRCA2-PALB2 complexes (D).
Figure 2
Figure 2
When an SSB occurs (A-1), PARP-1 recruits scaffold proteins and forms an ADP-ribose chain on itself (PARylation) using NAD+ (A-2). The PARylation also promotes PARP-1 dissociation and leads scaffold proteins to repair the SSB (A-3 and A-4). When an SSB occurs in presence of a PARPi (B-1), the PARPi binds the NAD+ binding site in a competitive way (B-2). Since the SSB cannot be repaired by PARP enzyme, the HRR system can repair the damage but the coexistence of HRD prevents the repair and induces cell death (B-3 and B-4).
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