Modeling Heterogeneity of Triple-Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance.

Autor: Lamballe F; Aix Marseille Univ CNRS Developmental Biology Institute of Marseille (IBDM) Turing Center for Living Systems Parc Scientifique de Luminy Marseille 13009 France., Ahmad F; Aix Marseille Univ CNRS Developmental Biology Institute of Marseille (IBDM) Turing Center for Living Systems Parc Scientifique de Luminy Marseille 13009 France., Vinik Y; Department of Molecular Cell Biology Weizmann Institute of Science Rehovot 76100 Israel., Castellanet O; Aix Marseille Univ CNRS Developmental Biology Institute of Marseille (IBDM) Turing Center for Living Systems Parc Scientifique de Luminy Marseille 13009 France., Daian F; Aix Marseille Univ CNRS Developmental Biology Institute of Marseille (IBDM) Turing Center for Living Systems Parc Scientifique de Luminy Marseille 13009 France., Müller AK; Department of Molecular Cell Biology Weizmann Institute of Science Rehovot 76100 Israel., Köhler UA; Department of Molecular Cell Biology Weizmann Institute of Science Rehovot 76100 Israel., Bailly AL; Aix Marseille Univ Centre de Recherche en Cancérologie de Marseille (CRCM) Equipes labellisées Ligue 'Cell polarity, cell signaling and cancer' and 'Telomere and Chromatin' Inserm CNRS Institut Paoli-Calmettes Marseille 13009 France., Josselin E; Aix Marseille Univ Inserm CNRS Institut Paoli-Calmettes CRCM TrGET Platform Marseille 13009 France., Castellano R; Aix Marseille Univ Inserm CNRS Institut Paoli-Calmettes CRCM TrGET Platform Marseille 13009 France., Cayrou C; Aix Marseille Univ Centre de Recherche en Cancérologie de Marseille (CRCM) Equipes labellisées Ligue 'Cell polarity, cell signaling and cancer' and 'Telomere and Chromatin' Inserm CNRS Institut Paoli-Calmettes Marseille 13009 France., Charafe-Jauffret E; Aix Marseille Univ Inserm CNRS Institut Paoli-Calmettes CRCM Experimental Histo-Pathology Platform Marseille 13009 France., Mills GB; Knight Cancer Institute Portland OR 97201 USA., Géli V; Aix Marseille Univ Centre de Recherche en Cancérologie de Marseille (CRCM) Equipes labellisées Ligue 'Cell polarity, cell signaling and cancer' and 'Telomere and Chromatin' Inserm CNRS Institut Paoli-Calmettes Marseille 13009 France., Borg JP; Aix Marseille Univ Centre de Recherche en Cancérologie de Marseille (CRCM) Equipes labellisées Ligue 'Cell polarity, cell signaling and cancer' and 'Telomere and Chromatin' Inserm CNRS Institut Paoli-Calmettes Marseille 13009 France.; Institut Universitaire de France (IUF) 1 rue Descartes Paris 75231 France., Lev S; Department of Molecular Cell Biology Weizmann Institute of Science Rehovot 76100 Israel., Maina F; Aix Marseille Univ CNRS Developmental Biology Institute of Marseille (IBDM) Turing Center for Living Systems Parc Scientifique de Luminy Marseille 13009 France.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2020 Dec 16; Vol. 8 (3), pp. 2003049. Date of Electronic Publication: 2020 Dec 16 (Print Publication: 2021).
DOI: 10.1002/advs.202003049
Abstrakt: Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model ( MMTV-R26 Met mice) of mammary tumors driven by a subtle increase in the expression of the wild-type MET receptor is generated. MMTV-R26 Met mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV-R26 Met tumors and machine learning approach show that the model faithfully recapitulates intertumoral heterogeneity of human TNBC. Further signaling network analysis highlights potential druggable targets, of which cotargeting of WEE1 and BCL-XL synergistically kills TNBC cells and efficiently induces tumor regression. Mechanistically, BCL-XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS 33 RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe, and apoptosis. This study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets.
Competing Interests: The authors declare no conflict of interest.
(© 2020 The Authors. Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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