Mitogen-activated protein kinase dependency in BRAF/RAS wild-type melanoma

a rationale for combination inhibitors

Zizhen Ming, Su Yin Lim, Richard F. Kefford, Helen Rizos*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway and immune checkpoint molecules have dramatically improved the survival of patients with BRAFV600-mutant melanoma. For BRAF/RAS wild-type (WT) melanoma patients, however, immune checkpoint inhibitors remain the only effective therapeutic option with 40% of patients responding to PD-1 inhibition. In the present study, a large panel of 10 BRAFV600-mutant and 13 BRAF/RAS WT melanoma cell lines was analyzed to examine MAPK dependency and explore the potential utility of MAPK inhibitors in this melanoma subtype. We now show that the majority of BRAF/RAS WT melanoma cell lines (8/13) display some degree of sensitivity to trametinib treatment and resistance to trametinib in this melanoma subtype is associated with, but not mediated by NF1 suppression. Although knockdown of NF1 stimulates RAS and CRAF activity, the activation of CRAF by NF1 knockdown is limited by ERK-dependent feedback in BRAF-mutant cells, but not in BRAF/RAS WT melanoma cells. Thus, NF1 is not a dominant regulator of MAPK signaling in BRAF/RAS WT melanoma, and co-targeting multiple MAP kinase nodes provides a therapeutic opportunity for this melanoma subtype.

Original languageEnglish
Pages (from-to)345-357
Number of pages13
JournalPigment Cell and Melanoma Research
Volume33
Issue number2
Early online date13 Sep 2019
DOIs
Publication statusPublished - Mar 2020

Keywords

  • MAPK
  • NF1
  • survival pathways
  • targeted therapies
  • trametinib
  • triple WT

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