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Cancer Cell. 2016 Jun 13;29(6):805-819. doi: 10.1016/j.ccell.2016.04.013. Epub 2016 May 26.

Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance.

Author information

1
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.
2
Institut de Chimie de Nice UMR UNS-CNRS 7272, Université Nice Sophia Antipolis, Parc Valrose, 06108 Nice cedex 2, France.
3
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.
4
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.
5
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.
6
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.
7
University Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, 59000 Lille, France.
8
Equipe Biophotonique Cellulaire Fonctionnelle, Laboratoire de Physique des Lasers, Atomes et Molécules (PhLAM) GDR 2588, 59658 Villeneuve d'Ascq, France.
9
Department of Dermatology, Cancer Campus, Gustave Roussy Institute, 114, rue Edouard-Vaillant, 94805 Villejuif, France.
10
Institute for Integrative Biology of the Cell (I2BC), CNRS CEA University Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette 91198, France.
11
INSERM, U1065, Team 8, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France.
12
Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
13
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.
14
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.

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.

Comment in

PMID:
27238082
DOI:
10.1016/j.ccell.2016.04.013
[Indexed for MEDLINE]
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