BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers

[en] 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.

Disciplines :

Oncology

Author, co-author :

Coussy, F.; Translational Research Department, Institut Curie, PSL Research University, Paris, 75005, France, Medical Oncology Department, Institut Curie, PSL Research University, Paris, 75005, France, Genetics Department, Institut Curie, PSL Research University, Paris, 75005, France

El-Botty, R.; Translational Research Department, Institut Curie, PSL Research University, Paris, 75005, France

Château-Joubert, S.; BioPôle Alfort, Ecole Nationale Vétérinaire d'Alfort, Maisons Alfort, 94704, France

Dahmani, A.; Translational Research Department, Institut Curie, PSL Research University, Paris, 75005, France

Montaudon, E.; Translational Research Department, Institut Curie, PSL Research University, Paris, 75005, France

Leboucher, S.; Institut Curie, PSL Research University, UMR3306, Orsay, 91405, France

Morisset, L.; Translational Research Department, Institut Curie, PSL Research University, Paris, 75005, France

Painsec, P.; Translational Research Department, Institut Curie, PSL Research University, Paris, 75005, France

Sourd, L.; Translational Research Department, Institut Curie, PSL Research University, Paris, 75005, France

Huguet, L.; Translational Research Department, Institut Curie, PSL Research University, Paris, 75005, France

More authors (24 more)

Language :

English

Title :

BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers

Publication date :

2020

Journal title :

Science Translational Medicine

ISSN :

1946-6234

eISSN :

1946-6242

Publisher :

American Association for the Advancement of Science

Volume :

Issue :

532

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

INCa-DGOS-Inserm_12554National Cancer Institute, NCI: BC-01-006161

Available on ORBi :

since 08 July 2020

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