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
Date
04/18/2021Pubmed ID
33865203DOI
10.1016/j.ejca.2021.01.055Scopus ID
2-s2.0-85104075728 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
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.
Author List
Kato S, Porter R, Okamura R, Lee S, Zelichov O, Tarcic G, Vidne M, Kurzrock RAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Aged, 80 and over
Antineoplastic Agents
Female
Genes, ras
Genetic Predisposition to Disease
Humans
MAP Kinase Kinase Kinases
Male
Middle Aged
Mitogen-Activated Protein Kinases
Mutation
Neoplasms
Phenotype
Protein Kinase Inhibitors
Signal Transduction
Time Factors