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Two decades of PARP inhibitor synthetic lethality in cancer

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Why This Matters

Over the past two decades, research into PARP inhibitors has revolutionized cancer therapy by exploiting synthetic lethality in BRCA-mutant tumors. This approach offers targeted treatment options, improving outcomes for patients with specific genetic vulnerabilities. The continued development of PARP inhibitors underscores their significance in advancing personalized cancer medicine and expanding therapeutic strategies.

Key Takeaways

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Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005). Together with Farmer et al. (2005), this study describes the discovery of the BRCA1/2 versus PARPi synthetic lethal effects.

Weinstein, I. B. Cancer. Addiction to oncogenes — the Achilles heal of cancer. Science 297, 63–64 (2002).

Hartwell, L. H., Szankasi, P., Roberts, C. J., Murray, A. W. & Friend, S. H. Integrating genetic approaches into the discovery of anticancer drugs. Science 278, 1064–1068 (1997).

Kaelin, W. G. Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 5, 689–698 (2005).

Brummelkamp, T. R. & Bernards, R. New tools for functional mammalian cancer genetics. Nat. Rev. Cancer 3, 781–789 (2003).

McCabe, N. et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 66, 8109–8115 (2006).

Schultz, N., Lopez, E., Saleh-Gohari, N. & Helleday, T. Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination. Nucleic Acids Res. 31, 4959–4964 (2003).

Moynahan, M. E., Cui, T. Y. & Jasin, M. Homology-directed DNA repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res. 61, 4842–4850 (2001).

Bhattacharyya, A., Ear, U. S., Koller, B. H., Weichselbaum, R. R. & Bishop, D. K. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J. Biol. Chem. 275, 23899–23903 (2000).

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