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

• Published in: Cancer cell Vol. 29; no. 6; pp. 805 - 819
• Main Authors: Cerezo, Michaël, Lehraiki, Abdelali, Millet, Antoine, Rouaud, Florian, Plaisant, Magali, Jaune, Emilie, Botton, Thomas, Ronco, Cyril, Abbe, Patricia, Amdouni, Hella, Passeron, Thierry, Hofman, Veronique, Mograbi, Baharia, Dabert-Gay, Anne-Sophie, Debayle, Delphine, Alcor, Damien, Rabhi, Nabil, Annicotte, Jean-Sébastien, Héliot, Laurent, Gonzalez-Pisfil, Mariano, Robert, Caroline, Moréra, Solange, Vigouroux, Armelle, Gual, Philippe, Ali, Maruf M.U., Bertolotto, Corine, Hofman, Paul, Ballotti, Robert, Benhida, Rachid, Rocchi, Stéphane
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.06.2016; Elsevier
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Resistance, Neoplasm - drug effects; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Humans; Life Sciences; Melanoma - drug therapy; Melanoma - metabolism; Mice; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Sulfonamides - administration & dosage; Sulfonamides - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2016.04.013

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. [Display omitted] •HA15 is a molecule that targets specifically BiP/GRP78/HSPA5•HA15 induces ER stress leading to cancer cell death in vitro and in vivo•HA15 overcomes BRAF inhibitor resistance in melanoma cells•HA15 is a potential therapeutic for melanoma treatment Cerezo et al. show that HA15, the lead compound of a series of thiazole benzenesulfonamides that they have developed, kills cancer cells by targeting BiP to increase ER stress. HA15 exhibits strong efficacy in melanoma cells, including those resistant to BRAF inhibitors.