Differential activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma
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Authors: | Matteo S Carlino Jason R Todd Kavitha Gowrishankar Branka Mijatov Gulietta M Pupo Carina Fung Stephanie Snoyman Peter Hersey Georgina V Long Richard F Kefford Helen Rizos |
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Institution: | 1. Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145, Australia;2. Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, New South Wales, Australia;3. Kolling Institute of Medical Research, University of Sydney, St. Leonards, New South Wales, Australia;4. Melanoma Institute Australia, Sydney, New South Wales, Australia;5. Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia |
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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. |
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Keywords: | ERK inhibitors BRAF inhibitors MEK inhibitors Melanoma Acquired resistance |
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