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Review
. 2022 Nov 16;14(22):5619.
doi: 10.3390/cancers14225619.

BMN673 Is a PARP Inhibitor with Unique Radiosensitizing Properties: Mechanisms and Potential in Radiation Therapy

Aashish Soni  1   2 , Xixi Lin  1   2 , Emil Mladenov  1   2 , Veronika Mladenova  1   2 , Martin Stuschke  1   3 , George Iliakis  1   2
Affiliations
Review

BMN673 Is a PARP Inhibitor with Unique Radiosensitizing Properties: Mechanisms and Potential in Radiation Therapy

Aashish Soni et al. Cancers (Basel). .

Abstract

BMN673 is a relatively new PARP inhibitor (PARPi) that exhibits superior efficacy in vitro compared to olaparib and other clinically relevant PARPi. BMN673, similar to most clinical PARPi, inhibits the catalytic activities of PARP-1 and PARP-2 and shows impressive anticancer potential as monotherapy in several pre-clinical and clinical studies. Tumor resistance to PARPi poses a significant challenge in the clinic. Thus, combining PARPi with other treatment modalities, such as radiotherapy (RT), is being actively pursued to overcome such resistance. However, the modest to intermediate radiosensitization exerted by olaparib, rucaparib, and veliparib, limits the rationale and the scope of such combinations. The recently reported strong radiosensitizing potential of BMN673 forecasts a paradigm shift on this front. Evidence accumulates that BMN673 may radiosensitize via unique mechanisms causing profound shifts in the balance among DNA double-strand break (DSB) repair pathways. According to one of the emerging models, BMN673 strongly inhibits classical non-homologous end-joining (c-NHEJ) and increases reciprocally and profoundly DSB end-resection, enhancing error-prone DSB processing that robustly potentiates cell killing. In this review, we outline and summarize the work that helped to formulate this model of BMN673 action on DSB repair, analyze the causes of radiosensitization and discuss its potential as a radiosensitizer in the clinic. Finally, we highlight strategies for combining BMN673 with other inhibitors of DNA damage response for further improvements.

Keywords: BMN673; DNA double strand breaks (DSB); DNA end-resection; DSB repair; PARP inhibitor; alt-EJ; c-NHEJ; error-prone DSB processing; homologous recombination; ionizing radiation; olaparib; radiosensitization; radiotherapy; talazoparib.

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Conflict of interest statement

Martin Stuschke: AstraZeneca (Advisory Board Function, Research and Clinical Trials), Bristol-Myers Squibb (Advisory Board Function), Sanofi-Aventis (Advisory Board Function) and Janssen-Cilag (Advisory Board Function). Other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Domain structure of human PARP-1, PARP-2, and PARP-3 proteins. The domain locations within the full-length proteins were extracted from the uniport database by using the following entries for PARP-1 (P09874), PARP-2 (Q9UGN5), and PARP-3 (Q9Y6F1). Main protein domains involved in DNA-binding, auto-modification, and catalytic functions are indicated. ZnFI: zinc finger I domain, ZnFII: zinc finger II domain, ZnFIII: zinc finger III domain, BRCT: BRCA1 C-terminal domain, WGR: Trp-Gly-Arg domain, HD: Helical domain, ART: (ADP-ribosyl) transferase domain. ZnFI and ZnFII help to recognize and bind to DNA damage sites, while ZnFIII activates the enzyme upon DNA binding. The BRCT domain of PARP-1 is required to localize XRCC1 and XRCC1-complexed DNA repair factors to DNA damage sites.
Figure 2
Figure 2
A central and critical role of PARP-1 in DNA repair. PARP-1 is the prime target of clinical PARPi and mediates multiple DNA repair processes (Please refer to Section 2 for details).
Figure 3
Figure 3
A model of altered DSB repair pathway balance at low and high IR doses in BMN673-treated cells. See text for details.
See this image and copyright information in PMC

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