title: Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance.
abstract: We have discovered and developed a series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti-cancerous activity on all melanoma cells tested, including cells isolated from patients and cells that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic, and biochemical studies identified the chaperone BiP/GRP78/HSPA5 as the specific target of HA15 and demonstrated that the interaction increases ER stress, leading to melanoma cell death by concomitant induction of autophagic and apoptotic mechanisms.
authors.affiliation: INSERM, U1065, Equipe Biologie et Pathologie des cellules mélanocytaire: de la pigmentation cutanée au mélanome, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France; UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France.
authors.forename: Michaël
authors.initials: M
authors.lastname: Cerezo
authors.affiliation: INSERM, U1065, Equipe Biologie et Pathologie des cellules mélanocytaire: de la pigmentation cutanée au mélanome, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France; UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France.
authors.forename: Abdelali
authors.initials: A
authors.lastname: Lehraiki
authors.affiliation: Institut de Chimie de Nice UMR UNS-CNRS 7272, Université Nice Sophia Antipolis, Parc Valrose, 06108 Nice cedex 2, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Millet
authors.affiliation: INSERM, U1065, Equipe Biologie et Pathologie des cellules mélanocytaire: de la pigmentation cutanée au mélanome, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France; UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Rouaud
authors.affiliation: INSERM, U1065, Equipe Biologie et Pathologie des cellules mélanocytaire: de la pigmentation cutanée au mélanome, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France; UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Plaisant
authors.affiliation: INSERM, U1065, Equipe Biologie et Pathologie des cellules mélanocytaire: de la pigmentation cutanée au mélanome, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France; UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Jaune
authors.affiliation: INSERM, U1065, Equipe Biologie et Pathologie des cellules mélanocytaire: de la pigmentation cutanée au mélanome, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France; UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Botton
authors.affiliation: Institut de Chimie de Nice UMR UNS-CNRS 7272, Université Nice Sophia Antipolis, Parc Valrose, 06108 Nice cedex 2, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Ronco
authors.affiliation: INSERM, U1065, Equipe Biologie et Pathologie des cellules mélanocytaire: de la pigmentation cutanée au mélanome, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France; UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Abbe
authors.affiliation: Institut de Chimie de Nice UMR UNS-CNRS 7272, Université Nice Sophia Antipolis, Parc Valrose, 06108 Nice cedex 2, France.
authors.forename: Hella
authors.initials: H
authors.lastname: Amdouni
authors.affiliation: INSERM, U1065, Equipe Biologie et Pathologie des cellules mélanocytaire: de la pigmentation cutanée au mélanome, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France; UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France; Service de Dermatologie, Hôpital Archet II, CHU, 06204 Nice, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Passeron
authors.affiliation: UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France; Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081, CNRS UMR7284, Nice 06107, France; Laboratoire de pathologie clinique et expérimentale et Hospital-related biobank (BB-0033-00025), Hôpital Pasteur, 06002 Nice, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Hofman
authors.affiliation: UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France; Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081, CNRS UMR7284, Nice 06107, France.
authors.forename: Baharia
authors.initials: B
authors.lastname: Mograbi
authors.affiliation: UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France; CNRS UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), 06560 Sophia Antipolis, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Dabert-Gay
authors.affiliation: UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France; CNRS UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), 06560 Sophia Antipolis, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Debayle
authors.affiliation: INSERM, U1065, Equipe Biologie et Pathologie des cellules mélanocytaire: de la pigmentation cutanée au mélanome, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France; UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Alcor
authors.affiliation: University Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, 59000 Lille, France.
authors.forename: Nabil
authors.initials: N
authors.lastname: Rabhi
authors.affiliation: University Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, 59000 Lille, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Annicotte
authors.affiliation: Equipe Biophotonique Cellulaire Fonctionnelle, Laboratoire de Physique des Lasers, Atomes et Molécules (PhLAM) GDR 2588, 59658 Villeneuve d'Ascq, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Héliot
authors.affiliation: Equipe Biophotonique Cellulaire Fonctionnelle, Laboratoire de Physique des Lasers, Atomes et Molécules (PhLAM) GDR 2588, 59658 Villeneuve d'Ascq, France.
authors.forename: Mariano
authors.initials: M
authors.lastname: Gonzalez-Pisfil
authors.affiliation: Department of Dermatology, Cancer Campus, Gustave Roussy Institute, 114, rue Edouard-Vaillant, 94805 Villejuif, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CNRS CEA University Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette 91198, France.
authors.forename: Solange
authors.initials: S
authors.lastname: Moréra
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CNRS CEA University Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette 91198, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Vigouroux
authors.affiliation: INSERM, U1065, Team 8, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gual
authors.affiliation: Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
authors.forename: Maruf M U
authors.initials: MMU
authors.lastname: Ali
authors.affiliation: INSERM, U1065, Equipe Biologie et Pathologie des cellules mélanocytaire: de la pigmentation cutanée au mélanome, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France; UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France; Service de Dermatologie, Hôpital Archet II, CHU, 06204 Nice, France.
authors.forename: Corine
authors.initials: C
authors.lastname: Bertolotto
authors.affiliation: UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France; Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081, CNRS UMR7284, Nice 06107, France; Laboratoire de pathologie clinique et expérimentale et Hospital-related biobank (BB-0033-00025), Hôpital Pasteur, 06002 Nice, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.affiliation: INSERM, U1065, Equipe Biologie et Pathologie des cellules mélanocytaire: de la pigmentation cutanée au mélanome, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France; UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France; Service de Dermatologie, Hôpital Archet II, CHU, 06204 Nice, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Ballotti
authors.affiliation: Institut de Chimie de Nice UMR UNS-CNRS 7272, Université Nice Sophia Antipolis, Parc Valrose, 06108 Nice cedex 2, France. Electronic address: benhida@unice.fr.
authors.forename: Rachid
authors.initials: R
authors.lastname: Benhida
authors.affiliation: INSERM, U1065, Equipe Biologie et Pathologie des cellules mélanocytaire: de la pigmentation cutanée au mélanome, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France; UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France; Service de Dermatologie, Hôpital Archet II, CHU, 06204 Nice, France. Electronic address: srocchi@unice.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Rocchi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D048493:Proto-Oncogene Proteins B-raf