Functional measurement of mitogen-activated protein kinase pathway activation predicts responsiveness of RAS-mutant cancers to MEK inhibitors

Eur J Cancer. 2021 May;149:184-192. doi: 10.1016/j.ejca.2021.01.055. Epub 2021 Apr 14.

Abstract

Background: RAS variant-related functional impact on the mitogen-activated protein kinase (MAPK) pathway, and correlation between MAPK activation and MAPK/ERK kinase (MEK) inhibitor responsiveness, is not established.

Patients and methods: Of 1,693 tumours sequenced, 576 harboured a RAS alteration; 62 patients received an MEK inhibitor (MEKi) and had RAS mutations that were functionally characterised. We report that RAS mutants have variable levels of MAPK activity, as measured by a functional cell-based assay that quantified MAPK pathway activation after transfection with a variety of RAS mutations.

Results: Patients with tumours harbouring RAS alterations with high versus low MAPK activity who were treated with an MEKi showed significantly longer median progression-free survival (PFS) (5.0 vs. 2.3 months; p = 0.0034) and overall survival (20.0 vs. 5.0 months; p = 0.0146) and a trend towards higher rates of clinical benefit (stable disease ≥6 months or partial/complete remission) (38% versus 15%; p = 0.095) (p-values as per univariate analysis). PFS remained statistically significant after the multivariate analysis (p = 0.003).

Conclusions: These results support a correlation between RAS-mutant cancers with greater MAPK signalling and PFS after MEKi treatment.

Trial registration: ClinicalTrials.gov NCT02478931.

Keywords: Cancer; MAPK activity; MEK inhibitor; RAS.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / therapeutic use*
  • Female
  • Genes, ras*
  • Genetic Predisposition to Disease
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Kinase Kinases / metabolism
  • Male
  • Middle Aged
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mutation*
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Neoplasms / mortality
  • Phenotype
  • Progression-Free Survival
  • Protein Kinase Inhibitors / therapeutic use*
  • Signal Transduction
  • Time Factors

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases

Associated data

  • ClinicalTrials.gov/NCT02478931