Differential activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma1. Issue 3 (15th January 2014)

• Record Type: Journal Article
• Authors: Carlino, Matteo S.; Todd, Jason R.; Gowrishankar, Kavitha; Mijatov, Branka; Pupo, Gulietta M.; Fung, Carina; Snoyman, Stephanie; Hersey, Peter; Long, Georgina V.; Kefford, Richard F.; Rizos, Helen
• Is Part Of: Molecular oncology. Volume 8:Issue 3(2014:May)
• Page Start: 544
• Page End: 554
• Publication Date: 2014-01-15
• Subjects: ERK inhibitors -- BRAF inhibitors -- MEK inhibitors -- Melanoma -- Acquired resistance; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1016/j.molonc.2014.01.003
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : Acquired resistance to BRAF inhibitors often involves MAPK re‐activation, yet the MEK inhibitor trametinib showed minimal clinical activity in melanoma patients that had progressed on BRAF‐inhibitor therapy. Selective ERK inhibitors have been proposed as alternative salvage therapies. We show that ERK inhibition is more potent than MEK inhibition at suppressing MAPK activity and inhibiting the proliferation of multiple BRAF inhibitor resistant melanoma cell models. Nevertheless, melanoma cells often failed to undergo apoptosis in response to ERK inhibition, because the relief of ERK‐dependent negative feedback activated RAS and PI3K signalling. Consequently, the combination of ERK and PI3K/mTOR inhibition was effective at promoting cell death in all resistant melanoma cell models, and was substantially more potent than the MEK/PI3K/mTOR inhibitor combination. Our data indicate that a broader targeting strategy concurrently inhibiting ERK, rather than MEK, and PI3K/mTOR may circumvent BRAF inhibitor resistance, and should be considered during the clinical development of ERK inhibitors. Highlights: We examine the activity of the MEK and ERK inhibition in models of melanoma BRAF inhibitor resistance. ERK inhibitors more efficiently suppress MAPK signalling in these models. Despite cell cycle arrest ERK inhibitors can only induce apoptosis in a subset of resistance models. Survival is due to ERK‐dependent negative feedback activated RAS and PI3K signalling. Combined ERK and PI3K/mTOR inhibition was effective at promoting cell death in all models.