MEK inhibitors in RASopathies

Curr Opin Oncol. 2021 Mar 1;33(2):110-119. doi: 10.1097/CCO.0000000000000711.


Purpose of review: An early understanding of the role of the Ras/Raf/MEK/ERK signalling pathway in regulating cell proliferation has set the stage for the development of several potent and selective MEK inhibitors (MEKi). MEKi represent promising therapies for RAS-driven neoplasias and RASopathies associated with increased Ras/MAPK activity.

Recent findings: Neurofibromatosis 1 (NF1) is a prototypic RASopathy in which early-phase clinical trials with MEKi have been successful in the treatment of plexiform neurofibromas (pNF) and low-grade gliomas (LGGs). The phase 2 trial (SPRINT) of selumetinib in pNF resulted in at least 20% reduction in the size of pNF from baseline in 71% of patients and was associated with clinically meaningful improvements. On the basis of this trial, selumetinib (Koselugo) received FDA approval for children 2 years of age and older with inoperable, symptomatic pNF. The phase 2 trial of selumetinib in LGG resulted in 40% partial response and 96% of patients had 2 years of progression-free survival.

Summary: Given the potential of MEK inhibition as an effective and overall well tolerated medical treatment, the use of targeted agents in the NF1 population is likely to increase considerably. Future work on non-NF1 RASopathies should focus on developing preclinical models and defining endpoints for measurement of efficacy in order to conduct clinical trials.

Trial registration: NCT03871257 NCT04166409.

Publication types

  • Review

MeSH terms

  • Animals
  • Clinical Trials, Phase II as Topic
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neurofibroma, Plexiform / drug therapy*
  • Neurofibroma, Plexiform / enzymology
  • Neurofibroma, Plexiform / metabolism
  • Neurofibromatosis 1 / drug therapy*
  • Neurofibromatosis 1 / enzymology
  • Neurofibromatosis 1 / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Randomized Controlled Trials as Topic
  • ras Proteins / metabolism


  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase Kinases
  • ras Proteins

Associated data