BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers
2020
Coussy, Florence | El-Botty, Rania | Château-Joubert, Sophie | Dahmani, Ahmed | Montaudon, Elodie | Leboucher, Sophie | Morisset, Ludivine | Painsec, Pierre | Sourd, Laura | Huguet, Léa | Nemati, Fariba | Servely, Jean-Luc | Larcher, Thibaut | Vacher, Sophie | Briaux, Adrien | Reyes, Cécile | La Rosa, Philippe | Lucotte, Georges | Popova, Tatiana | Foidart, Pierre | Sounni, Nor Eddine | Noel, Agnès | Decaudin, Didier | Fuhrmann, Laetitia | Salomon, Anne | Reyal, Fabien | Mueller, Christopher | ter Brugge, Petra | Jonkers, Jos | Poupon, Marie-France | Stern, Marc-Henri | Bièche, Ivan | Pommier, Yves | Marangoni, Elisabetta | Translational Research Department,Medical Oncology Department, Genetics Department ; Institut Curie [Paris] | Translational Research Department ; Institut Curie [Paris] | Biopôle Alfort ; École nationale vétérinaire d'Alfort (ENVA) | Signalisation, neurobiologie et cancer - Signalisation cellulaire et neurobiologie (SNC) ; Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) | Département Physiologie Animale et Systèmes d'Elevage (PHASE) ; Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) | École nationale vétérinaire d'Alfort (ENVA) | Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher) ; École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) | Genetics Department ; Universidade de Santiago de Compostela [España] = University of Santiago de Compostela [Spain] = Université de Saint-Jacques-de-Compostelle [Espagne] (USC) | Université Paris Sciences et Lettres (PSL) | Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe ; Mines Paris - PSL (École nationale supérieure des mines de Paris) ; Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM) | U830 ; Institut National de la Santé et de la Recherche Médicale (INSERM) | Laboratory of Tumor and Developmental Biology ; Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer) | Université de Liège = University of Liège = Universiteit van Luik = Universität Lüttich (ULiège) | Laboratory of Tumor and Developmental Biology ; Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer) | Translational Research Department, Medical Oncology Department ; Institut Curie [Paris] | Department of Pathology ; University of Veterinary and Animal Sciences, Lahore | Surgery Department ; Centre Paul Strauss (CRLCC Paul Strauss) ; UNICANCER-UNICANCER | Immunité et cancer (U932) ; Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM) | Queen's cancer reserach institute | Queen's University | Division of Molecular Pathology and Cancer Genomics Centre Netherlands ; Netherlands Cancer Institute | Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute ; National Institutes of Health [Bethesda, MD, USA] (NIH)
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.
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