BIOMARKERS

Why BRCA mutations are not tumour-agnostic biomarkers for PARP inhibitor therapy

Article metrics

BRCA1/2 mutations and poly (ADP-ribose) polymerase (PARP) inhibitors are paradigmatic of synthetic lethal therapy. However, the activity of PARP inhibitors seems to vary considerably across BRCA1/2-mutant cancers and new insights into the tumour-lineage dependency of this synthetic lethal relationship might explain why BRCA1/2 mutations are not tumour-agnostic biomarkers of a response to PARP inhibitors.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Bryant, H. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).

  2. 2.

    Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

  3. 3.

    Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

  4. 4.

    Jonsson, P. et al. Tumour lineage shapes BRCA-mediated phenotypes. Nature 571, 576–579 (2019).

  5. 5.

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

  6. 6.

    Lindahl, T. Instability and decay of the primary structure of DNA. Nature 362, 709–715 (1993).

  7. 7.

    Mukhopadhyay, A. et al. Development of a functional assay for homologous recombination status in primary cultures of epithelial ovarian tumor and correlation with sensitivity to poly(ADP-ribose) polymerase inhibitors. Clin. Cancer Res. 16, 2344–2351 (2010).

  8. 8.

    Sakai, W. et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451, 1116–1120 (2008).

  9. 9.

    Bunting, S. F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010).

  10. 10.

    Coleman, R. L. et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390, 1949–1961 (2017).

  11. 11.

    Gelmon, K. et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 12, 852–861 (2011).

Download references

Author information

Correspondence to Nicola J. Curtin.

Ethics declarations

Competing interests

N.J.C. has received research funding from Aguoron Pharmaceuticals and Pfizer for the development of rucaparib, from BioMarin for studies of talazoparib and from Tesaro for studies of niraparib. N.J.C. has also been paid by Abbvie for consultancy relating to the development of veliparib. N.J.C. is an inventor on the patent relating to the use of rucaparib in homologous recombination repair-deficient cancer, and Newcastle University receives royalty income from the sales of rucaparib that are shared with contributors to its development, including N.J.C. and Y.D. Y.D. has received research grant funding from AstraZeneca, Clovis Oncology and Tesaro and has participated in scientific advisory boards for AstraZeneca, Clovis Oncology, Merck and Tesaro. Y.D. is also a principal investigator of clinical trials of olaparib and rucaparib. S.S.-S. declares no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Curtin, N.J., Drew, Y. & Sharma-Saha, S. Why BRCA mutations are not tumour-agnostic biomarkers for PARP inhibitor therapy. Nat Rev Clin Oncol (2019) doi:10.1038/s41571-019-0285-2

Download citation