دورية أكاديمية
BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers
| العنوان: | BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers |
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| المؤلفون: | Coussy, F., El-Botty, R., Château-Joubert, S., Dahmani, A., Montaudon, E., Leboucher, S., Morisset, L., Painsec, P., Sourd, L., Huguet, L., Nemati, F., Servely, J.-L., Larcher, T., Vacher, S., Briaux, A., Reyes, C., La Rosa, P., Lucotte, G., Popova, T., Foidart, Pierre, Sounni, Nor Eddine, Noël, Agnès, Decaudin, D., Fuhrmann, L., Salomon, A., Reyal, F., Mueller, C., Brugge, P. T., Jonkers, J., Poupon, M.-F., Stern, M.-H., Bièche, I., Pommier, Y., Marangoni, E. |
| المصدر: | Science Translational Medicine, 12 (532) (2020) |
| بيانات النشر: | American Association for the Advancement of Science |
| سنة النشر: | 2020 |
| المجموعة: | University of Liège: ORBi (Open Repository and Bibliography) |
| مصطلحات موضوعية: | DNA topoisomerase inhibitor, Article, BRCAness gene, RB1 gene, SLFN11 gene, Human health sciences, Oncology, Sciences de la santé humaine, Oncologie |
| الوصف: | peer reviewed ; Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors. Copyright © 2020 The Authors, some rights reserved. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1946-6234 1946-6242 |
| العلاقة: | urn:issn:1946-6234; urn:issn:1946-6242; https://orbi.uliege.be/handle/2268/249408Test; info:hdl:2268/249408; scopus-id:2-s2.0-85079795061; info:pmid:32075943 |
| DOI: | 10.1126/scitranslmed.aax2625 |
| الإتاحة: | https://doi.org/10.1126/scitranslmed.aax2625Test https://orbi.uliege.be/handle/2268/249408Test |
| حقوق: | restricted access ; http://purl.org/coar/access_right/c_16ecTest ; info:eu-repo/semantics/restrictedAccess |
| رقم الانضمام: | edsbas.6C1FBE28 |
| قاعدة البيانات: | BASE |
| تدمد: | 19466234 19466242 |
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| DOI: | 10.1126/scitranslmed.aax2625 |