Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers
Open accessAbstract
Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown. Here we show that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast-cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, Capan-1 (refs 3, 4), led to five different secondary mutations that restored the wild-type BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP) inhibitor (AG14361). Finally, we evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumour that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Our results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy.
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Mutational scars represent genomic history and not current on-going mutational processes that can result in false positive CHORD predictions.
“We do acknowledge that mutational scars represent genomic history and not current on-going mutational processes that can result in false positive CHORD predictions, which could be for example due to reversion of HRD by secondary frameshifts34,35, or recent acquisition of the HRD phenotype.”
From Pan-cancer landscape of homologous recombination deficiency. (2020) · cites this paper as [34]
Cites
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N. J., Johnson, D. A., Richardson, T. B., Santarosa, M., Dillon, K. J., Hickson, I., Knights, C., et al. (2005) · Nature · doi:10.1038/nature03445 · Cited by 6,683 · see citing works
Interaction of the Fanconi Anemia Proteins and BRCA1 in a Common Pathway
Garcia-Higuera, I., Taniguchi, T., Ganesan, S., Meyn, M. S., Timmers, C., Hejna, J., Grompe, M., & D'Andrea, A. D. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00173-3 · Cited by 1,198 · see citing works
Self-citationFanconi anemia is associated with a defect in the BRCA2 partner PALB2
Xia, B., Dorsman, J. C., Ameziane, N., de Vries, Y., Rooimans, M. A., Sheng, Q., Pals, G., Errami, A., Gluckman, E., Llera, J., et al. (2007) · Nature Genetics · doi:10.1038/ng1942 · Cited by 465 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Cancer drug resistance: an evolving paradigm
Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3599 · Cited by 4,681 · see citing works
Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from <i>BRCA</i> Mutation Carriers
Fong, P. C., Boss, D. S., Yap, T. A., Tutt, A., Wu, P., Mergui-Roelvink, M., Mortimer, P., Swaisland, H., Lau, A., O'Connor, M. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0900212 · Cited by 3,634 · see citing works
Molecular mechanisms of cisplatin resistance
Galluzzi, L., Senovilla, L., Vitale, I., Michels, J., Martins, I., Kepp, O., Castedo, M., & Kroemer, G. (2012) · Oncogene · doi:10.1038/onc.2011.384 · Cited by 2,760 · see citing works
Audeh, M. W., Carmichael, J., Penson, R. T., Friedlander, M., Powell, B., Bell-McGuinn, K. M., Scott, C., Weitzel, J. N., Oaknin, A., Loman, N., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60893-8 · Cited by 2,279 · see citing works
Principles of cancer therapy: oncogene and non-oncogene addiction
Luo, J., Solimini, N. L., & Elledge, S. J. (2009) · Cell · doi:10.1016/j.cell.2009.02.024 · Cited by 1,765 · see citing works
53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks
Bunting, S. F., Callén, E., Wong, N., Chen, H.-T., Polato, F., Gunn, A., Bothmer, A., Feldhahn, N., Fernandez-Capetillo, O., Cao, L., et al. (2010) · Cell · doi:10.1016/j.cell.2010.03.012 · Cited by 1,671 · see citing works
Tutt, A., Robson, M., Garber, J. E., Domchek, S. M., Audeh, M. W., Weitzel, J. N., Friedlander, M., Arun, B., Loman, N., Schmutzler, R. K., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60892-6 · Cited by 1,655 · see citing works
PARP inhibition: PARP1 and beyond
Rouleau, M., Patel, A., Hendzel, M. J., Kaufmann, S. H., & Poirier, G. G. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2812 · Cited by 1,298 · see citing works
Lord, C. J., & Ashworth, A. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2015.21 · Cited by 1,257 · see citing works
HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures
Davies, H., Glodzik, D., Morganella, S., Yates, L. R., Staaf, J., Zou, X., Ramakrishna, M., Martin, S., Boyault, S., Sieuwerts, A. M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4292 · Cited by 1,086 · see citing works
DNA repair dysregulation from cancer driver to therapeutic target
Curtin, N. J. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3399 · Cited by 1,051 · see citing works
Shen, D.-W., Pouliot, L. M., Hall, M. D., & Gottesman, M. M. (2012) · Pharmacological Reviews · doi:10.1124/pr.111.005637 · Cited by 955 · see citing works
Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer
Konstantinopoulos, P. A., Ceccaldi, R., Shapiro, G. I., & D'Andrea, A. D. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0714 · Cited by 945 · see citing works
Sun, Y., Campisi, J., Higano, C., Beer, T. M., Porter, P., Coleman, I., True, L., & Nelson, P. S. (2012) · Nature Medicine · doi:10.1038/nm.2890 · Cited by 793 · see citing works
Systems biology of cisplatin resistance: past, present and future
Galluzzi, L., Vitale, I., Michels, J., Brenner, C., Szabadkai, G., Harel-Bellan, A., Castedo, M., & Kroemer, G. (2014) · Cell Death & Disease · doi:10.1038/cddis.2013.428 · Cited by 782 · see citing works
Microhomology-Mediated End Joining: A Back-up Survival Mechanism or Dedicated Pathway?
Sfeir, A., & Symington, L. S. (2015) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.08.006 · Cited by 636 · see citing works
The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance
Bouwman, P., & Jonkers, J. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3342 · Cited by 615 · see citing works
PARP inhibition elicits STING-dependent antitumor immunity in brca1-deficient ovarian cancer
Ding, L., Kim, H.-J., Wang, Q., Kearns, M., Jiang, T., Ohlson, C. E., Li, B. B., Xie, S., Liu, J. F., Stover, E. H., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.11.054 · Cited by 572 · see citing works
“Underlying HR deficiency is important for the cytotoxicity of PARP inhibitors, and this is highlighted by the fact that the most prevalent mechanism of PARP inhibitor resistance in HR-deficient tumors is secondary genetic and epigenetic events that functionally revert the original HR alteration and restore HR proficie…”
BackgroundPan-cancer landscape of homologous recombination deficiency.
Nguyen, L., W. M. Martens, J., Van Hoeck, A., & Cuppen, E. (2020) · Nature communications · doi:10.1038/s41467-020-19406-4 · Cited by 532 · see citing works
“mutational processes that can result in false positive CHORD predictions, which could be for example due to reversion of HRD by secondary frameshifts[35, 36], or recent acquisition of the HRD phenotype.”
BackgroundTherapeutic applications of PARP inhibitors: Anticancer therapy and beyond
Curtin, N. J., & Szabo, C. (2013) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2013.01.006 · Cited by 369 · see citing works
Vaidyanathan, A., Sawers, L., Gannon, A.-L., Chakravarty, P., Scott, A. L., Bray, S. E., Ferguson, M. J., & Smith, G. (2016) · British Journal of Cancer · doi:10.1038/bjc.2016.203 · Cited by 364 · see citing works
Biomarkers for Homologous Recombination Deficiency in Cancer
Hoppe, M. M., Sundar, R., Tan, D. S. P., & Jeyasekharan, A. D. (2018) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/djy085 · Cited by 329 · see citing works
Watkins, J. A., Irshad, S., Grigoriadis, A., & Tutt, A. N. (2014) · Breast Cancer Research · doi:10.1186/bcr3670 · Cited by 327 · see citing works
BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers
Maxwell, K. N., Wubbenhorst, B., Wenz, B. M., De Sloover, D., Pluta, J., Emery, L., Barrett, A., Kraya, A. A., Anastopoulos, I. N., Yu, S., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00388-9 · Cited by 296 · see citing works
Konstantinopoulos, P. A., Barry, W. T., Birrer, M., Westin, S. N., Cadoo, K. A., Shapiro, G. I., Mayer, E. L., O'Cearbhaill, R. E., Coleman, R. L., Kochupurakkal, B., et al. (2019) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30905-7 · Cited by 263 · see citing works
Self-citationGeyer, F. C., Weigelt, B., Natrajan, R., Lambros, M. B., de Biase, D., Vatcheva, R., Savage, K., Mackay, A., Ashworth, A., & Reis‐Filho, J. S. (2010) · The Journal of Pathology · doi:10.1002/path.2675 · Cited by 233 · see citing works
PARP inhibitors: review of mechanisms of action and BRCA1/2 mutation targeting
Dziadkowiec, K. N., Gąsiorowska, E., Nowak-Markwitz, E., & Jankowska, A. (2016) · Menopausal Review · doi:10.5114/pm.2016.65667 · Cited by 191 · see citing works
KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer
Burgess, M. R., Hwang, E., Mroue, R., Bielski, C. M., Wandler, A. M., Huang, B. J., Firestone, A. J., Young, A., Lacap, J. A., Crocker, L., et al. (2017) · Cell · doi:10.1016/j.cell.2017.01.020 · Cited by 183 · see citing works
Mechanisms of BRCA1 Tumor Suppression
Silver, D. P., & Livingston, D. M. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0221 · Cited by 159 · see citing works
Schoonen, P. M., Kok, Y. P., Wierenga, E., Bakker, B., Foijer, F., Spierings, D. C. J., & van Vugt, M. A. T. M. (2019) · Molecular Oncology · doi:10.1002/1878-0261.12573 · Cited by 81 · see citing works
Li, M., Lin, A., Luo, P., Shen, W., Xiao, D., Gou, L., Zhang, J., & Guo, L. (2020) · Aging · doi:10.18632/aging.102683 · Cited by 62 · see citing works
Understanding Resistance Mechanisms and Expanding the Therapeutic Utility of PARP Inhibitors
Lim, J., & Tan, D. S. P. (2017) · Cancers · doi:10.3390/cancers9080109 · Cited by 52 · see citing works
Funingana, I.-G., Reinius, M. A. V., Petrillo, A., Ang, J. E., & Brenton, J. D. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.02.008 · Cited by 23 · see citing works
- Authors
- Sakai, W., Swisher, E. M., Karlan, B. Y., Agarwal, M. K., Higgins, J., Friedman, C., Villegas, E., Jacquemont, C., Farrugia, D. J., Couch, F. J., Urban, N., & Taniguchi, T.
- Affiliations
- Fred Hutch Cancer Center (US)
- University of Washington (US)
- Cedars-Sinai Medical Center (US)
- Mayo Clinic (US)
- Corresponding author
- Taniguchi, Toshiyasu
- ORCID
- Venue
- Nature
- Published
- 2008-02
- Volume
- 451
- Issue
- 7182
- Pages
- 1116-1120
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2577037
- OpenAlex
- W2067117419
- Cited by
- 1,086
- References
- 3
- Citations by year
- 2026: 35 · 2025: 43 · 2024: 53 · 2023: 55 · 2022: 73 · 2021: 101 · 2020: 65 · 2019: 55 · 2018: 60 · 2017: 76 · 2016: 59 · 2015: 42 · 2014: 52 · 2013: 50 · 2012: 62
- FWCI
- 38.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- authors@Fred Hutch (Fred Hutchinson Cancer Research Center) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (5p50ca083636-15)
- National Cancer Institute (P50-CA083636, K08CA096610, R01CA125636)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- cisplatin resistance, BRCA2 mutation, secondary mutations, acquired drug resistance, platinum-based chemotherapy, ovarian cancer, breast cancer, pancreatic cancer, PARP inhibitors, homologous recombination, DNA repair, reading frame restoration, recurrent tumor
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Benzodiazepines, Breast Neoplasms, Cisplatin, Female, Humans, Middle Aged, Mutation, Neoplasms, Ovarian Neoplasms, Pancreatic Neoplasms, Drug Resistance, Neoplasm, Genes, BRCA2, BRCA2 Protein, Cell Line, Tumor, Azulenes
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