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Review
. 2021 Aug 17;13(16):4132.
doi: 10.3390/cancers13164132.

Recent Advances in Enhancing the Therapeutic Index of PARP Inhibitors in Breast Cancer

Camille Franchet  1 , Jean-Sébastien Hoffmann  2 , Florence Dalenc  3
Affiliations
Review

Recent Advances in Enhancing the Therapeutic Index of PARP Inhibitors in Breast Cancer

Camille Franchet et al. Cancers (Basel). .

Abstract

As poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with the deficiency of DNA double-strand (DSB) break repair by homologous recombination (HR), PARP inhibitors (PARPi) are currently used to treat breast cancers with mutated BRCA1/2 HR factors. Unfortunately, the increasingly high rate of PARPi resistance in clinical practice has dented initial hopes. Multiple resistance mechanisms and acquired vulnerabilities revealed in vitro might explain this setback. We describe the mechanisms and vulnerabilities involved, including newly identified modes of regulation of DSB repair that are now being tested in large cohorts of patients and discuss how they could lead to novel treatment strategies to improve the therapeutic index of PARPi.

Keywords: PARP inhibitor; breast cancer; homologous recombination deficiency; resistance.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Synthetic representation of PARP inhibitors resistance mechanisms. Abbreviation: DSB = Double strand break; HR = Homologous recombination; LOH = Loss of heterozygosity; NHEJ = Non-homologous end-joining; PARP = Poly(ADP-ribose) polymerase; PARPi = PARP inhibitors; SSB = Single strand break; TMEJ = Theta-mediated end-joining.
Figure 2
Figure 2
Therapeutic strategies to target DDR. Abbreviation: DSBs = Double-strand breaks.
Figure 3
Figure 3
Rationale for targeting theta-mediated end joining (TMEJ) in PARPi-resistant breast cancers. The poly(ADP-ribose) polymerase (PARP) is responsible for the repair of single-stranded DNA (ssDNA) breaks. The PARP inhibitors inhibit the catalytic activity of PARP and can trap PARP proteins on the DNA. These bulky complexes impede the progression of DNA replication forks, which stall, leads to unloading of the replicative helicase and DNA polymerases, and creates a single-ended DSB. When a converging fork is coming, a double-ended DSB is generated. This DSB can be resolved by a functional HR machinery, leading to cell survival. When HR is defective, the damage persists, leading to cell death. One mechanism explaining primary or secondary resistance to PARPi relies on the activation of the alternative Polθ-mediated End-Joining (TMEJ) DSB repair pathway which can rescue HR defect. Abbreviations: HR = homologous recombination; ssDNA = single-stranded DNA.
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References

    1. Li J., Wen W.X., Eklund M., Kvist A., Eriksson M., Christensen H.N., Torstensson A., Bajalica-Lagercrantz S., Dunning A.M., Decker B., et al. Prevalence of BRCA1 and BRCA2 Pathogenic Variants in a Large, Unselected Breast Cancer Cohort: BRCA Testing for All Breast Cancer Patients? Int. J. Cancer. 2019;144:1195–1204. doi: 10.1002/ijc.31841. - DOI - PMC - PubMed
    1. Hu C., Polley E.C., Yadav S., Lilyquist J., Shimelis H., Na J., Hart S.N., Goldgar D.E., Shah S., Pesaran T., et al. The Contribution of Germline Predisposition Gene Mutations to Clinical Subtypes of Invasive Breast Cancer From a Clinical Genetic Testing Cohort. J. Natl. Cancer Inst. 2020;112:1231–1241. doi: 10.1093/jnci/djaa023. - DOI - PMC - PubMed
    1. Hu C., Hart S.N., Gnanaolivu R., Huang H., Lee K.Y., Na J., Gao C., Lilyquist J., Yadav S., Boddicker N.J., et al. A Population-Based Study of Genes Previously Implicated in Breast Cancer. N. Engl. J. Med. 2021;384:440–451. doi: 10.1056/NEJMoa2005936. - DOI - PMC - PubMed
    1. Ece Solmaz A., Yeniay L., Gökmen E., Zekioğlu O., Haydaroğlu A., Bilgen I., Özkınay F., Onay H. Clinical Contribution of Next-Generation Sequencing Multigene Panel Testing for BRCA Negative High-Risk Patients With Breast Cancer. Clin. Breast Cancer. 2021 doi: 10.1016/j.clbc.2021.04.002. - DOI - PubMed
    1. Lang G.-T., Shi J.-X., Huang L., Cao A.-Y., Zhang C.-H., Song C.-G., Zhuang Z.-G., Hu X., Huang W., Shao Z.-M. Multiple Cancer Susceptible Genes Sequencing in BRCA-Negative Breast Cancer with High Hereditary Risk. Ann. Transl. Med. 2020;8:1417. doi: 10.21037/atm-20-2999. - DOI - PMC - PubMed