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1. Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers

Author

Rania El-Botty, Ludivine Morriset, Elodie Montaudon, Zakia Tariq, Anne Schnitzler, Marina Bacci, Nicla Lorito, Laura Sourd, Léa Huguet, Ahmed Dahmani, Pierre Painsec, Heloise Derrien, Sophie Vacher, Julien Masliah-Planchon, Virginie Raynal, Sylvain Baulande, Thibaut Larcher, Anne Vincent-Salomon, Guillaume Dutertre, Paul Cottu, Géraldine Gentric, Fatima Mechta-Grigoriou, Scott Hutton, Keltouma Driouch, Ivan Bièche, Andrea Morandi, and Elisabetta Marangoni

Subjects
Science
Abstract

Abstract Resistance to endocrine treatments and CDK4/6 inhibitors is considered a near-inevitability in most patients with estrogen receptor positive breast cancers (ER + BC). By genomic and metabolomics analyses of patients’ tumours, metastasis-derived patient-derived xenografts (PDX) and isogenic cell lines we demonstrate that a fraction of metastatic ER + BC is highly reliant on oxidative phosphorylation (OXPHOS). Treatment by the OXPHOS inhibitor IACS-010759 strongly inhibits tumour growth in multiple endocrine and palbociclib resistant PDX. Mutations in the PIK3CA/AKT1 genes are significantly associated with response to IACS-010759. At the metabolic level, in vivo response to IACS-010759 is associated with decreased levels of metabolites of the glutathione, glycogen and pentose phosphate pathways in treated tumours. In vitro, endocrine and palbociclib resistant cells show increased OXPHOS dependency and increased ROS levels upon IACS-010759 treatment. Finally, in ER + BC patients, high expression of OXPHOS associated genes predict poor prognosis. In conclusion, these results identify OXPHOS as a promising target for treatment resistant ER + BC patients.

Published
2023
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2. PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance

Author

Elodie Montaudon, Joanna Nikitorowicz-Buniak, Laura Sourd, Ludivine Morisset, Rania El Botty, Léa Huguet, Ahmed Dahmani, Pierre Painsec, Fariba Nemati, Sophie Vacher, Walid Chemlali, Julien Masliah-Planchon, Sophie Château-Joubert, Camilla Rega, Mariana Ferreira Leal, Nikiana Simigdala, Sunil Pancholi, Ricardo Ribas, André Nicolas, Didier Meseure, Anne Vincent-Salomon, Cécile Reyes, Audrey Rapinat, David Gentien, Thibaut Larcher, Mylène Bohec, Sylvain Baulande, Virginie Bernard, Didier Decaudin, Florence Coussy, Muriel Le Romancer, Guillaume Dutertre, Zakia Tariq, Paul Cottu, Keltouma Driouch, Ivan Bièche, Lesley-Ann Martin, and Elisabetta Marangoni

Subjects
Science
Abstract

Identifying novel therapies for the treatment of CDK4/6 inhibitor-resistant patients is of great importance. Here, the authors demonstrate that PLK1 inhibition is a potential therapeutic target in CCND1-driven and in RB-positive Palbociclib-resistant breast cancers.

Published
2020
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3. PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance

Author

Zakia Tariq, Sunil Pancholi, Nikiana Simigdala, Thibaut Larcher, Virginie Bernard, Mariana Ferreira Leal, Sophie Château-Joubert, Camilla Rega, Muriel Le Romancer, Fariba Nemati, Didier Decaudin, Ludivine Morisset, Anne Vincent-Salomon, Rania El Botty, Elisabetta Marangoni, Ahmed Dahmani, Cécile Reyes, Walid Chemlali, Audrey Rapinat, Ricardo Ribas, Guillaume Dutertre, Didier Meseure, Lesley-Ann Martin, Paul Cottu, Elodie Montaudon, Julien Masliah-Planchon, Sophie Vacher, Keltouma Driouch, Joanna Nikitorowicz-Buniak, Laura Sourd, Léa Huguet, Florence Coussy, Mylène Bohec, André Nicolas, Sylvain Baulande, Ivan Bièche, Pierre Painsec, David Gentien, Translational Research Department, Institut Curie, PSL Research University, Paris 75248, France, The institute of cancer research [London], Service de génétique, Institut Curie Paris, École nationale vétérinaire d'Alfort (ENVA), Department of pathology, Institut Curie, Institut Curie [Paris], Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Expertise en Anatomie Pathologique (APEX), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Genomics of Excellence (ICGex) Platform, Institut Curie Research Center, Department of Medical Oncology, Institut Curie, Paris 75248, France, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie/ Departement de chirurgie/ 26 rue d'Ulm/ 75005 Paris, École nationale vétérinaire - Alfort (ENVA), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and BABARIT, Candice

Subjects
0301 basic medicine, Pyridines, General Physics and Astronomy, Cell Cycle Proteins, 02 engineering and technology, Piperazines, Transcriptome, Mice, Breast cancer, Cyclin D1, lcsh:Science, Exome sequencing, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, Pteridines, 021001 nanoscience & nanotechnology, Immunohistochemistry, 3. Good health, G2 Phase Cell Cycle Checkpoints, 0210 nano-technology, medicine.drug, DNA Copy Number Variations, Science, Immunoblotting, Anastrozole, Mice, Nude, Breast Neoplasms, Palbociclib, Protein Serine-Threonine Kinases, PLK1, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Targeted therapies, Cell Line, Tumor, Proto-Oncogene Proteins, Exome Sequencing, medicine, Animals, Humans, Immunoprecipitation, Cancer models, neoplasms, Cell growth, business.industry, General Chemistry, medicine.disease, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer research, lcsh:Q, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

A significant proportion of patients with oestrogen receptor (ER) positive breast cancers (BC) develop resistance to endocrine treatments (ET) and relapse with metastatic disease. Here we perform whole exome sequencing and gene expression analysis of matched primary breast tumours and bone metastasis-derived patient-derived xenografts (PDX). Transcriptomic analyses reveal enrichment of the G2/M checkpoint and up-regulation of Polo-like kinase 1 (PLK1) in PDX. PLK1 inhibition results in tumour shrinkage in highly proliferating CCND1-driven PDX, including different RB-positive PDX with acquired palbociclib resistance. Mechanistic studies in endocrine resistant cell lines, suggest an ER-independent function of PLK1 in regulating cell proliferation. Finally, in two independent clinical cohorts of ER positive BC, we find a strong association between high expression of PLK1 and a shorter metastases-free survival and poor response to anastrozole. In conclusion, our findings support clinical development of PLK1 inhibitors in patients with advanced CCND1-driven BC, including patients progressing on palbociclib treatment., Identifying novel therapies for the treatment of CDK4/6 inhibitor-resistant patients is of great importance. Here, the authors demonstrate that PLK1 inhibition is a potential therapeutic target in CCND1-driven and in RB-positive Palbociclib-resistant breast cancers.

Published
2020
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4. BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers

Author

Petra ter Brugge, Laetitia Fuhrmann, Fabien Reyal, Rania El-Botty, Thibaut Larcher, Laura Sourd, Sophie Château-Joubert, Agnès Noël, Jean-Luc Servely, Léa Huguet, Ivan Bièche, Pierre Foidart, Jos Jonkers, Philippe La Rosa, Pierre Painsec, Sophie Leboucher, Ludivine Morisset, Fariba Nemati, Georges Lucotte, Elodie Montaudon, Didier Decaudin, Christopher R. Mueller, Florence Coussy, Ahmed Dahmani, Marc-Henri Stern, Marie-France Poupon, Nor Eddine Sounni, Sophie Vacher, Adrien Briaux, Yves Pommier, Anne Vincent Salomon, Elisabetta Marangoni, Cécile Reyes, Tatiana Popova, Translational Research Department,Medical Oncology Department, Genetics Department, Institut Curie, Translational Research Department, BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), PSL Research University, UMR3306, Département Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Ecole 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, University of Santiago de Compostela, Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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, Translational Research Department, Medical Oncology Department, Department of Pathology, University of Veterinary and Animal Sciences, Lahore, Surgery Department, CRLCC Paul Strauss, U932, Immunity and Cancer, 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, ProdInra, Archive Ouverte, École nationale vétérinaire - Alfort (ENVA), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universidade de Santiago de Compostela [Spain] (USC ), 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), Biologie du développement et reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Développement et Pathologie du Tissu Musculaire (DPTM), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), PSL Research University, U900, and Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes

Subjects
Anthracycline, DNA repair, Ubiquitin-Protein Ligases, [SDV]Life Sciences [q-bio], Triple Negative Breast Neoplasms, Topoisomerase-I Inhibitor, Irinotecan, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, CHEK1, skin and connective tissue diseases, 030304 developmental biology, 0303 health sciences, biology, Retinoblastoma, business.industry, Topoisomerase, Nuclear Proteins, General Medicine, medicine.disease, eye diseases, 3. Good health, [SDV] Life Sciences [q-bio], Retinoblastoma Binding Proteins, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Topoisomerase I Inhibitors, business, Schlafen family member 11, medicine.drug
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.

Published
2020
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5. Response to mTOR and PI3K inhibitors in enzalutamide-resistant luminal androgen receptor triple-negative breast cancer patient-derived xenografts

Author

Leanne De Koning, Thibaut Larcher, Bérengère Ouine, Ivan Bièche, Rania El Botty, Anne Vincent Salomon, Ahmed Dahmani, Florence Coussy, Jean Marc Guinebretière, Walid Chemlali, Adrien Briaux, Sophie Chateau-Joubert, Marion Lavigne, Sophie Vacher, Samia Melaabi, Guillaume Bataillon, Adnan Naguez, Elodie Montaudon, Elisabetta Marangoni, Pierre Painsec, Fuhrmann Laetitia, Fariba Nemati, Unit of Pharmacogenomics, Department of Genetics,Laboratory of Preclinical Investigation, Department of Translational Research, Department of Medical Oncology, Institut Curie, Department of Biopathology, Università degli Studi di Roma Tor Vergata [Roma], Translational Research Department, RPPA Platform, Institut Curie Research Center, Laboratory of Preclinical Investigation, Department of Translational Research, BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Unit of Pharmacogenomics, Department of Genetics, U1016, Institut National de la Santé et de la Recherche Médicale (INSERM), ProdInra, Archive Ouverte, École nationale vétérinaire - 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), Expertise en Anatomie Pathologique (APEX), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Curie [Paris], Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0301 basic medicine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), AKT1, luminal androgen receptor (LAR), Triple Negative Breast Neoplasms, Targeted therapy, chemistry.chemical_compound, 0302 clinical medicine, androgen receptor, Molecular Targeted Therapy, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Triple-negative breast cancer, Phosphoinositide-3 Kinase Inhibitors, Aged, 80 and over, TOR Serine-Threonine Kinases, Middle Aged, targeted therapy, 3. Good health, [SDV] Life Sciences [q-bio], Receptors, Androgen, 030220 oncology & carcinogenesis, Benzamides, Heterografts, Female, Research Paper, Signal Transduction, Adult, Biology, 03 medical and health sciences, Cytokeratin, Breast cancer, PI3K pathway inhibitor, Nitriles, Phenylthiohydantoin, medicine, Humans, Enzalutamide, genomic alteration, Protein Kinase Inhibitors, PI3K/AKT/mTOR pathway, Aged, medicine.disease, Androgen receptor, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, Mutation, Cancer research
Abstract

Luminal androgen receptor (LAR) breast cancer accounts for 10% of all triple-negative breast cancers (TNBC). Anti-androgen therapy for this subtype is in development, but yields only partial clinical benefits. In this study, we aimed to characterize the genomic alterations of LAR TNBC, to analyze activation of the PI3K signaling pathway and to compare the response to PI3K pathway inhibitors with that to anti-androgen therapy in patient-derived xenografts (PDX) of LAR TNBC. Methods: Four LAR PDX models were identified, on the basis of their transcriptomic profiles, in a cohort of 57 PDX models of TNBC. The expression of AR-related genes, basal and luminal cytokeratins and EMT genes was analyzed by RT-PCR and IHC. AKT1 and PIK3CA mutations were identified by targeted NGS, and activation of the PI3K pathway was analyzed with a reverse-phase protein array. Three LAR PDXs with a PIK3CA or AKT1 mutation were treated with the AR inhibitor enzalutamide, a PI3K inhibitor, a dual PI3K-mTOR inhibitor and a mTORC1-mTORC2 inhibitor. Finally, we screened a clinical cohort of 329 TNBC for PIK3CA and AKT1 hotspot mutations. Results: LAR TNBC PDXs were significantly enriched in PIK3CA and AKT1 mutations, and had higher levels of luminal-androgen-like gene expression and a higher PI3K pathway protein activation score than other TNBC subtypes. Immunohistochemistry analysis revealed strong expression of the luminal cytokeratin CK18 and AR in three LAR PDX models. We found that mTOR and PI3K inhibitors had marked antitumor activity in vivo in PDX harboring genomic alterations of PIK3CA and AKT1 genes that did not respond to the AR antagonist enzalutamide. PIK3CA mutations were detected in more than one third of AR+ TNBC from patients (38%), and only 10% of AR-negative TNBC. Conclusion: Our results for PDX models of LAR TNBC resistant to enzalutamide indicate that PIK3CA and AKT1 are potential therapeutic targets.

Published
2020
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6. Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancers

Author

Ahmed Dahmani, Adrien Briaux, L. De Koning, Ivan Bièche, Samia Melaabi, C. Gu, Marion Lavigne, Elodie Montaudon, Sophie Vacher, R. El Botty, Léa Huguet, Laura Sourd, Ludivine Morisset, Pierre Painsec, Laetitia Fuhrmann, A. Vincent Salomon, Elisabetta Marangoni, S. Chateau-Joubert, Thibaut Larcher, Florence Coussy, Unit of Pharmacogenomics, Department of Genetics,Laboratory of Preclinical Investigation, Department of Translational Research,Department of Medical Oncology, Institut Curie, Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie Research Center, Department of Biopathology, Università degli Studi di Roma Tor Vergata [Roma], Unit of Pharmacogenomics, Department of Genetics, Translational Research Department, RPPA Platform, BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, U1016, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Institut Curie [Paris], École nationale vétérinaire - 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), Expertise en Anatomie Pathologique (APEX), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ProdInra, Archive Ouverte, Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0301 basic medicine, MAPK/ERK pathway, Cancer Research, [SDV]Life Sciences [q-bio], AKT1, Triple Negative Breast Neoplasms, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, skin and connective tissue diseases, Phosphoinositide-3 Kinase Inhibitors, Aged, 80 and over, Hematology, MEK inhibitor, TOR Serine-Threonine Kinases, lcsh:Diseases of the blood and blood-forming organs, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, Stem cell, hormones, hormone substitutes, and hormone antagonists, Signal Transduction, Adult, medicine.medical_specialty, endocrine system, Class I Phosphatidylinositol 3-Kinases, Short Report, Mice, Nude, Antineoplastic Agents, Metaplastic breast cancer, PI3K inhibitor, Biology, lcsh:RC254-282, digestive system, 03 medical and health sciences, Breast cancer, Internal medicine, medicine, Animals, Humans, Combination of targeted therapies, Molecular Biology, Protein Kinase Inhibitors, neoplasms, PI3K/AKT/mTOR pathway, Aged, Mitogen-Activated Protein Kinase Kinases, lcsh:RC633-647.5, Fibroblast growth factor receptor 4, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, Mutation, Cancer research, Proto-Oncogene Proteins c-akt
Abstract

Background Metaplastic breast cancer (MBC) is a rare form of breast cancer characterized by an aggressive clinical presentation, with a poor response to standard chemotherapy. MBCs are typically triple-negative breast cancers (TNBCs), frequently with alterations to genes of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. The objective of this study was to determine the response to PI3K and MAPK pathway inhibitors in patient-derived xenografts (PDXs) of MBCs with targetable alterations. Methods We compared survival between triple-negative MBCs and other histological subtypes, in a clinical cohort of 323 TNBC patients. PDX models were established from primary breast tumors classified as MBC. PI3K-AKT-mTOR and RTK-MAPK pathway alterations were detected by targeted next-generation sequencing (NGS) and analyses of copy number alterations. Activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways was analyzed with reverse-phase protein arrays (RPPA). PDXs carrying an activating mutation of PIK3CA and genomic changes to the RTK-MAPK signaling pathways were treated with a combination consisting of a PI3K inhibitor and a MEK inhibitor. Results In our clinical cohort, the patients with MBC had a worse prognosis than those with other histological subtypes. We established nine metaplastic TNBC PDXs. Three had a pathogenic mutation of PIK3CA and additional alterations to genes associated with RTK-MAPK signaling. The MBC PDXs expressed typical EMT and stem cell genes and were of the mesenchymal or mesenchymal stem-like TNBC subtypes. On histological analysis, MBC PDXs presented squamous or chondroid differentiation. RPPA analysis showed activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. In vivo, the combination of PI3K and MAPK inhibitors displayed marked antitumor activity in PDXs carrying genomic alterations of PIK3CA, AKT1, BRAF, and FGFR4. Conclusion The treatment of metaplastic breast cancer PDXs by activation of the PI3K-AKT-mTOR and RTK-MAPK pathways at the genomic and protein levels with a combination of PI3K and MEK inhibitors resulted in tumor regression in mutated models and may therefore be of interest for therapeutic purposes.

Published
2020
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7. A large collection of integrated genomically characterized patient‐derived xenografts highlighting the heterogeneity of triple‐negative breast cancer

Author

Cécile Laurent, Gaëlle Pierron, Marion Lavigne, Pierre Painsec, Ivan Bièche, Elisabetta Marangoni, Cécile Reyes, Ahmed Dahmani, Bérengère Ouine, David Gentien, Leanne De Koning, Laura Sourd, Elodie Montaudon, Anne Vincent-Salomon, Ludivine Morisset, Florence Coussy, Samia Melaabi, Franck Assayag, Thibaut Larcher, Sylvain Baulande, Elodie Girard, Céline Callens, Léa Huguet, Sophie Chateau-Joubert, Virginie Bernard, Véronique Diéras, Jean-Luc Servely, Rania El Botty, Anais Boulai, Sophie Vacher, Institut Curie, Institut Curie Research Center (Laboratory of Preclinical Investigation, Department of Translational Research), Translational Research Department, RPPA Platform, Institut Curie Research Center, Department of Biopathology, Università degli Studi di Roma Tor Vergata [Roma], Unit of Pharmacogenomics, Department of Genetics, Laboratory of Preclinical Investigation, Department of Translational Research, aboratory of Preclinical Investigation, Department of Translational Research, BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), Développement et Pathologie du Tissu Musculaire (DPTM), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), Translational Research Department, Genomics Platform, U900, Institut National de la Santé et de la Recherche Médicale (INSERM), Unit of Somatic Genomics, Department of Genetics, Rt2 Lab, Genomics of Excellence (ICGex) Platform, Institut Curie Research, Department of Medical Oncology, Humanitas Centro Catanese di Oncologia, Inserm U1016, Paris Descartes University, Institut Curie [Paris], Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, and 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)

Subjects
Neuroblastoma RAS viral oncogene homolog, endocrine system, Cancer Research, Combination therapy, Class I Phosphatidylinositol 3-Kinases, [SDV]Life Sciences [q-bio], Gene Dosage, Triple Negative Breast Neoplasms, Biology, GTP Phosphohydrolases, Genetic Heterogeneity, Mice, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Animals, Humans, Gene Regulatory Networks, Molecular Targeted Therapy, Precision Medicine, Biomarker discovery, skin and connective tissue diseases, Gene, PI3K/AKT/mTOR pathway, Triple-negative breast cancer, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Membrane Proteins, Middle Aged, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, Cancer research, Immunohistochemistry, Female, Tumor Suppressor Protein p53, Neoplasm Transplantation, Signal Transduction
Abstract

Triple-negative breast cancer (TNBC) represents 10% of all breast cancers and is a very heterogeneous disease. Globally, women with TNBC have a poor prognosis, and the development of effective targeted therapies remains a real challenge. Patient-derived xenografts (PDX) are clinically relevant models that have emerged as important tools for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX (n = 61) in order to test targeted therapies and identify biomarkers of response. At the gene expression level, TNBC PDX represent all of the various TNBC subtypes identified by the Lehmann classification except for immunomodulatory subtype, which is underrepresented in PDX. NGS and copy number data showed a similar diversity of significantly mutated gene and somatic copy number alteration in PDX and the Cancer Genome Atlas TNBC patients. The genes most commonly altered were TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways. PDX showed similar morphology and immunohistochemistry markers to those of the original tumors. Efficacy experiments with PI3K and MAPK inhibitor monotherapy or combination therapy showed an antitumor activity in PDX carrying genomic mutations of PIK3CA and NRAS genes. TNBC PDX reproduce the molecular heterogeneity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research.

Published
2019
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8. Abstract 925: PDX models of ER+ endocrine-resistant metastatic breast cancer identify Polo-like kinase 1 (PLK1) as a therapeutic target

Author

Guillaume Dutertre, Zakia Tariq, Didier Meseure, Sunil Pancholi, Elodie Montaudon, André Nicolas, Paul Cottu, Fariba Nemati, Ludivine Morriset, Joanna Nikitorowicz-Buniak, Rania El Botty, Elisabetta Marangoni, Sophie Chateau-Joubert, Ahmed Dahmani, Laura Sourd, Anne Vincent Salomon, Ricardo Ribas, Keltouma Driouch, Camilla Rega, Ivan Bièche, Pierre Painsec, Lesley-Ann Martin, Sophie Vacher, Léa Huguet, and Florence Coussy

Subjects
Cancer Research, Fulvestrant, business.industry, Cancer, Bone metastasis, Mitotic nuclear division, Volasertib, Palbociclib, medicine.disease, Metastatic breast cancer, Primary tumor, chemistry.chemical_compound, Oncology, chemistry, medicine, Cancer research, business, medicine.drug
Abstract

Background: Metastatic estrogen receptor positive (ER+) breast cancers (BC) are genetically heterogeneous and a significant proportion of patients display intrinsic or acquired resistance to endocrine treatments, mTOR and CDK4/6 inhibitors. The objective of this study was to identify new therapies in clinically relevant PDX models of metastatic ER+ BC progressing on endocrine treatment and/or palbociclib. Methods: PDX models were generated by engraftment of spinal bone metastases from 120 BC patients. PDXs were molecularly characterized using SNP-arrays, targeted exome sequencing and global gene expression (GEX) analysis. The anti-tumor efficacy of the PLK1 inhibitor volasertib was evaluated in vivo compared to fulvestrant and palbociclib in two PDX models. PLK1 abundance was analyzed by immunohistochemistry in PDXs and compared with the original primary tumor and bone metastasis from each patient. PLK1 expression measured by RT-PCR was assessed in a cohort of 441 BC patients with 15-year follow-up. GEX analysis of PLK1was assessed in patients treated with neoadjuvant anastrazole. Mechanistic studies were performed in a panel of endocrine resistant BC cell lines. Results: Ten PDX have been established, 8 were ER+ and 2 triple-negative (TN). Genomic alterations included mutations in AKT1, PI3KCA, BRCA2, GATA3, NF1, and amplifications of FGFR1, CCND1 and CCNE2. Comparative pathway analysis of bone metastases derived PDX and patients' primary tumors showed enrichment for pathways associated with mitotic nuclear division, chromatid segregation and G2/M transition. PLK1 was the top commonly up-regulated gene within these pathways. Treatment of an endocrine-resistant ER+ PDX, harboring amplification of CCND1, CCNE2, FGFR1 and high expression of CDK1, showed only partial response to palbociclib and resistance to the FGFR inhibitor, AZD4547. However, PLK1 inhibitor volasertib induced rapid tumor shrinkage and complete response within 5 weeks. Importantly, volasertib was also highly effective when tested as second line therapy in palbociclib pre-treated xenografts. In-vitro inhibition of PLK1 by siRNA or volasertib inhibited tumor proliferation without affecting the expression of ER-regulated genes, suggesting an ER-independent function of PLK1 in regulating cell proliferation. Assessment of the clinical validity of PLK1 expression, revealed a strong association with poor metastases free survival (p Conclusion: We show that inhibition of PLK1 is a new potential treatment strategy for metastatic ER+ BC. Additional experiments are ongoing in PDX and cell lines to investigate G2/M phase dependence of ER+ BC and to identify predictive biomarkers. Citation Format: Elodie Montaudon, Joanna Nikitorowicz-Buniak, Laura Sourd, Rania El Botty, Ahmed Dahmani, Léa Huguet, Ludivine Morriset, Pierre Painsec, Fariba Nemati, Sophie Vacher, Sophie Chateau-Joubert, Sunil Pancholi, Camilla Rega, Ricardo Ribas, André Nicolas, Didier Meseure, Anne Salomon, Zakia Tariq, Keltouma Driouch, Florence Coussy, Guillaume Dutertre, Paul Cottu, Ivan Bièche, Lesley-Ann Martin, Elisabetta Marangoni. PDX models of ER+ endocrine-resistant metastatic breast cancer identify Polo-like kinase 1 (PLK1) as a therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 925.

Published
2019
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