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Updated: May 17, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

SHOC2 and CRAF mediate ERK1/2 reactivation in mutant NRAS-mediated resistance to RAF inhibitor

Fred M Kaplan1, Curtis H Kugel, Neda Dadpey

  • 1Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

The Journal of Biological Chemistry
|October 19, 2012
PubMed

Insights

NRAS mutations can cause resistance to BRAF inhibitors like vemurafenib in melanoma by reactivating ERK1/2 signaling. This resistance involves altered RAF isoform and scaffold protein requirements, highlighting new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • BRAF mutations are common in melanoma, and BRAF inhibitors show efficacy.
  • However, resistance to BRAF inhibitors often occurs due to ERK1/2 pathway reactivation.
  • Mechanisms of resistance, particularly involving NRAS, are not fully understood.

Purpose of the Study:

  • To investigate how NRAS mutations contribute to resistance against BRAF inhibitors in melanoma.
  • To elucidate the molecular mechanisms underlying ERK1/2 pathway reactivation in resistant cells.
  • To identify potential therapeutic strategies to overcome BRAF inhibitor resistance.

Main Methods:

  • Generated BRAF(V600E) melanoma cells co-expressing NRAS(Q61K) to model resistance.
  • Utilized PLX4720 (a vemurafenib tool compound) to assess drug response.
  • Analyzed ERK1/2 pathway activation, cell cycle progression (S phase), and apoptosis.
  • Investigated the roles of RAF isoforms (CRAF) and scaffold proteins (SHOC-2/Sur-8).

Main Results:

  • NRAS(Q61K) expression in BRAF(V600E) cells conferred resistance to PLX4720 by reactivating ERK1/2 signaling.
  • NRAS-mediated resistance bypassed PLX4720 effects on cell cycle and apoptosis.
  • ERK1/2 activation in resistant cells required CRAF and was modulated by SHOC-2/Sur-8.
  • A switch in RAF isoform requirement (CRAF) was observed during drug treatment.

Conclusions:

  • NRAS mutations are a key mechanism of resistance to BRAF inhibitors in BRAF-mutant melanoma.
  • Reactivation of the ERK1/2 pathway by NRAS involves altered RAF isoform and scaffold protein dependencies.
  • Targeting NRAS or downstream effectors may overcome BRAF inhibitor resistance.

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