Cancer Cell
Volume 29, Issue 6, 13 June 2016, Pages 805-819
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Article
Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance

https://doi.org/10.1016/j.ccell.2016.04.013Get rights and content
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Highlights

  • 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

Summary

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.

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