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CANCER THERAPY

In Polϴ position

Nature Reviews Cancer volume 21, page 540 (2021)Cite this article

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Inactivation of the genes BRCA1 or BRCA2, among others, causes cancers with a deficiency in homologous recombination (HR)-mediated DNA repair. As a consequence, these cancers depend upon alternative pathways of DNA repair to safeguard DNA replication, which by virtue of being dispensable to normal cells represent a therapeutic vulnerability. The DNA polymerase Polϴ is one such protein involved in backup DNA repair, and its genetic targeting selectively induces cell death in HR-deficient tumours as a result of synthetic lethality. However, the lack of development of inhibitors of Polϴ for preclinical testing has dampened its potential as a translatable target. Now two independent groups led by D’Andrea and Lord have identified and characterized two first-in-class specific inhibitors of Polϴ.

PARP also directs alternative DNA repair, compensating for the absence of HR in several cancer types. Recognition of this synthetic lethal interaction led to the development of PARP inhibitors (PARPi), which have had significant clinical success. Yet, acquired resistance to these drugs is emerging, justifying the need for new therapeutic possibilities. Interestingly, using their in vivo models, which included a PARPi-resistant ovarian cancer PDX, Zhou et al. showed that the combination of NVB and the PARPi olaparib synergistically reduced tumour growth.

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References

Original article

  • Zatreanu, D. et al. Polϴ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat. Commun. 12, 3636 (2021)

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  • Zhou, J. et al. A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. Nat. Cancer 2, 598–610 (2021)

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  1. Nature Reviews Cancer http://www.nature.com/nrc/

    Anna Dart

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  1. Anna Dart
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Correspondence to Anna Dart.

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Dart, A. In Polϴ position. Nat Rev Cancer 21, 540 (2021). https://doi.org/10.1038/s41568-021-00394-6

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