2. Academic Validation
  3. BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers

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

  • Sci Transl Med. 2020 Feb 19;12(531):eaax2625. doi: 10.1126/scitranslmed.aax2625.
Florence Coussy 1 2 3,  Rania El-Botty 1,  Sophie Château-Joubert 4,  Ahmed Dahmani 1,  Elodie Montaudon 1,  Sophie Leboucher 5,  Ludivine Morisset 1,  Pierre Painsec 1,  Laura Sourd 1,  Léa Huguet 1,  Fariba Nemati 1,  Jean-Luc Servely 4 6,  Thibaut Larcher 7,  Sophie Vacher 3,  Adrien Briaux 3,  Cécile Reyes 1,  Philippe La Rosa 8 9,  Georges Lucotte 8 9,  Tatiana Popova 9 10,  Pierre Foidart 11,  Nor Eddine Sounni 11,  Agnès Noel 11,  Didier Decaudin 1 2,  Laetitia Fuhrmann 12,  Anne Salomon 12,  Fabien Reyal 13 14,  Christopher Mueller 15,  Petra Ter Brugge 16,  Jos Jonkers 16,  Marie-France Poupon 1,  Marc-Henri Stern 9 10,  Ivan Bièche 3,  Yves Pommier 17,  Elisabetta Marangoni 18
Affiliations

Affiliations

  • 1 Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France.
  • 2 Medical Oncology Department, Institut Curie, PSL Research University, 75005 Paris, France.
  • 3 Genetics Department, Institut Curie, PSL Research University, 75005 Paris, France.
  • 4 BioPôle Alfort, Ecole Nationale Vétérinaire d'Alfort, 94704 Maisons Alfort, France.
  • 5 Institut Curie, PSL Research University, UMR3306, 91405 Orsay, France.
  • 6 INRA, PHASE Department, 37380 Nouzilly, France.
  • 7 INRA, APEX-PAnTher, Oniris, 44300 Nantes, France.
  • 8 INSERM, U900, 75005 Paris, France.
  • 9 Institut Curie, PSL Research University, 75005 Paris, France.
  • 10 INSERM U830, 75005 Paris, France.
  • 11 Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), University of Liège, Liège 4000, Belgium.
  • 12 Department of Pathology, Institut Curie, PSL Research University, 75005 Paris, France.
  • 13 Surgery Department, Institut Curie, PSL Research University, 75005 Paris, France.
  • 14 U932, Immunity and Cancer, INSERM, Institut Curie, 75005 Paris, France.
  • 15 Queen's Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada.
  • 16 Division of Molecular Pathology and Cancer Genomics Centre Netherlands, Netherlands Cancer Institute, Amsterdam, 1066 CX, Netherlands.
  • 17 Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. elisabetta.marangoni@curie.fr pommier@nih.gov.
  • 18 Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France. elisabetta.marangoni@curie.fr pommier@nih.gov.
PMID: 32075943 DOI: 10.1126/scitranslmed.aax2625
Abstract

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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