Differential activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma

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*

*Corresponding author for this work

Research output: Contribution to journalArticle

78 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)544-554
Number of pages11
JournalMolecular Oncology
Volume8
Issue number3
DOIs
Publication statusPublished - May 2014
Externally publishedYes

Keywords

  • Acquired resistance
  • BRAF inhibitors
  • ERK inhibitors
  • MEK inhibitors
  • Melanoma

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