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

Publication date: Available online 26 May 2016
Source:Cancer Cell
Author(s): Michaël Cerezo, Abdelali Lehraiki, Antoine Millet, Florian Rouaud, Magali Plaisant, Emilie Jaune, Thomas Botton, Cyril Ronco, Patricia Abbe, Hella Amdouni, Thierry Passeron, Veronique Hofman, Baharia Mograbi, Anne-Sophie Dabert-Gay, Delphine Debayle, Damien Alcor, Nabil Rabhi, Jean-Sébastien Annicotte, Laurent Héliot, Mariano Gonzalez-Pisfil, Caroline Robert, Solange Moréra, Armelle Virougoux, Philippe Gual, Maruf M.U. Ali, Corine Bertolotto, Paul Hofman, Robert Ballotti, Rachid Benhida, Stéphane Rocchi
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.

Graphical abstract

Teaser

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.


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